JC + MO + SC mix

Lovastatin

• cyp3A4 substrate- highly lipophilic

Simvastatin

• cyp3A4 substrate— highly lipophilic.

• Added steric bulk with two CH3 (isopropyl(?)) to lessen ester hydrolysis in gut.

Pravastatin

• more polar due to OH = less 3A4 metabolism by kidney

• Less potent

• Has open ring to readily bind / not a prodrug.

Fluvastatin synthetic

• open OH chain to COOH binds mevalonate site

• lipophilic anchor binds cholesterol site (stops after double bond)

• Added fluorine, heterocyclic ring with isopropyl group, weird pentagon

Atorvastatin

• LONG t1/2 due to slow metabolism of lipophilic anchor

• fluorine, heterocyclic ring with N, and amine group on lipophilic anchor for cholesterol binding site

Rosuvastatin aka SUPERSTATIN

• Sulfone group very lipopholic substituent

Pitavastatin

• Alien triangle comes off of N-heterocycle

• Weaker vs atorva/rosuva

Ezetemibe- cholesterol absorption inhibitor

• beta lactam square boi with =o covalently binds to target

This inhibits annexin1/caveolin1 transport protein complex in GI Which normally binds to Nieman Pick receptor.

• can’t bind NPC1L1 = decrease serum cholesterol and liver cholesterol esters

Why does it make sense that statins will effectively inhibit the biosynthesis of cholesterol?

The shape of the molecule allows for the lipophilic section to anchor into the cholesterol site & the hydrophilic chain to bind the mevalonate site.

1. Occupation of cholesterol binding site

2. Cascade can’t continue

3. Less cholesterol biosynthesis

Bempedoic Acid— ATP citrate lyase inhibitor

• symmetrical prodrug with methyls alpha to COOH to avoid stepwise b-oxidation metabolism

• converted to active form= added acetyl coA

• ACoA is long with phosphate, pentagon, then double ring with 5N

Colestipol— Bile Acid Sequestrant

• polymer

• N has H+ when it becomes protonated in HCl within stomach. This is why we avoid with use of PPI, H2ant, ca carb

Bile acid biosynthesis: RLS and features

Bile acid synthesis accounts for 90% cholesterol use and eventually becomes waste

• RLS is cholesterol-7a hydroxylase which adds OH to B ring

• Eventually becomes an ampiphilic molecule with its ability to conjugate with AA which have ionized terminuses

Ampiphilicity of bile acids

• Lipid parts: grab fats

• polar AA part: keep dispersed in water; usually glycine or taurine

  rx target: solubilize fats in aqueous environment to eliminate more cholesterol in poo

How do bile acids work: example cholestyramine

BAS like cholestyramine are LONG CHAIN ion exchange resins that are too big to be absorbed. exchange Cl- for bile acid negative terminus.

• yes we are exchanging negative for negative here but that is because there is a stronger attraction between bile acid- than Cl- (to drug)

• always has 4* ammonium so no activation

  Weird texture may deter use for patients

Colesevelam— bile acid sequestrant

• HETEROPOLYMER

• Tablet 3tab BID

• Less interactions, more palatable

What is one consideration to take when giving bile acid sequestrants

ALL highly negatively charged drugs can bind by mistake (unintended consequences)

• statin

• warfarin, thyroid hormones

• NSAID

• Fat sol vitamins ADEK

Niacin / nicotinic acid

Agonizes small Gi to inhibit cAMP & acts as PPAR activator (activate LPL for degradation)

• decreased mobilization of FA

• XR = less flushing, can minimize flushing with NSAID

gemfibrozil— fibrate

• double methyl alpha to COOH prevents beta oxidation metabolism

• COOH provides binding

• Chain of X length = receptor activation

• Acid (?)

• Medium level effectiveness at enhancing LPL

Because fibrates are PPAR activators; what other effects do they have

More lipids processed = lesser lipid conc

insulin sensitizing

Lipid homeostasis by reducing TG and mid level blood glucose lowering

fenofibrate— fibrate (ester prodrug)

Cl, benzene, =o, benzene with ether chain to eater and isopropyl

• Cleavage of isopropyl ester: yields active form with COOH terminus

• Gemini twins still here (geminal dimethyl) to reduce B-oxidation metabolism.

Fibrate considerations

• acid form highly lipophilic highly protein bound

• Enterohepatic recycling - increase t1/2

• Elimination limited: free acids or cool glucuronides in urine or bile

Orlistat: intestinal lipase inhibitor

Reactive Square boi with O but different from ezetimibe because there’s no F on molecule

• Mimics glycerol

• Ester chain

• Binds and blocks as false substrate to serine on intestinal enzyme = poop out fats instead of absorb

eicosapentaenoic acid 20:5 — omega 3 FA

• chain linkages: eskimos had better lipid profiles eating lots of fish fats

• Less sticky fats, less sticky plaques

inclisiran siRNA

Modification of nucleic acids to add: fluorine or OMe

(MO) response to inhibition of chokesterol absorption by ezetimibe

• decreased chylomicron synthesis & remnant transport to liver

• INCREASED LDL RECEPTOR EXPRESSION

• INCREASED CHOLESTEROL SYNTHESIS (hmg coa REDUCTASE increase)

• Blocks apical NPC1L1

MO ezetimibe rat

Inhibits absorption of cholesterol when bound to apical NPC1L1

• usually acts to package ApoB100 into chylomicrons

• When inhibited with ezetimibe: decreased cholesterol transport to liver & upreg of LDL-r

(MO rat) Statin pleiotropy

Inhibit statins =

• decrease cholesterol biosynthesis

• reduced FA molecules that are used in the prenylation of small G protein ATPases so they cant get to location or function right

• Equals helpful CV effects- disruption of VSMC proliferation and migration

ACLi: Bempedoic Acid MOA

Prodrug

• activation by ACS

works upstream of HMG CoA reductase but only act in liver and fat

• no skeletal muscle action means no myopathy

(MO rat) Bile Acid Sequestrant MOA

Nonsystemic Inhibition of the reabsorption of cholesterol by

• keeping them in the GI tract (JC ion exchange resin AA- in exchange for Cl-)

• Increase LDL-r expression

Fibrates: PPAR activators interaction

Statins especially gen fibrosis cause myopathy in combo

Which decrease enterohepatic recycling

Bile acid sequestrants

Niacin MOA / SE

Increase HDL via increased ApoA-I

• causes flushing bc prostaglandin release and niacin GPCR

• Can minimize with aspirin/nsaids

Omega 3 FA MOA

Decrease triglycerides

• Decrease VLDL synthesis

• Increase b-oxidation of FA

• increase LPL activity

PCSK9i: Moab MOA

AKA PCSK9 degraders:

Attach to PCSK9 antigen on the surface of LDL receptors to inhibit degradation by lysosomes

indirect PCSK9i: inclisiran MOA

modify nucleic acids of sugar phosphate backbone by adding fluorine or OMe group to disguise it from enzyme bounty hunters which mark for degradation. Because the antisense strand can not bind to the enzyme bounty hunters, it will combine with RISC instead. RISC-RNA inducing silencing complex— will then inhibit translation of PCSK9. Thus there will be more LDL-receptor recycling and more LDL-c uptake.

(SC RAT) atherogenesis

LDL enters intimal layer of blood vessel & oxidizes to become trapped & promote a good environment for adhesion molecules

• O-LDL becomes ligand for scavenger molecules expressed by macrophages (used to be monocytes)

• Phagocytize to foam cells

T cells secrete cytokines & macrophages

• cytokines make EC become proinflammatory and activate more macrophages

• SMC migrates to become part of plaque

(SC RAT) NO made by eNOS

Atheroprotective

• vasodilation

• Inhibition of platelet aggregation

• Inhibition of monocyte adhesion

• Inhibits SMC migration + proliferation

• Inhibits oxidized LDL

(SC RAT) ABI to test for PAD

Good: 1.1-1.25

Bad: over 1.4, under 0.9