dyslipidemia medicinal chemistry

what are the three functions of cholesterol

-structural component of the cell membrane

-starting material to synthesize steroid hormones

-starting material to synthesize bile acids/salts

what are the two things that bile acids are important for

-digestion and absorption of fats and fat soluble vitamins from the diet in the small intestine

-important for regulating blood cholesterol levels

where are the two places that cholesterol comes from

-our diet

-synthesis of it from scratch in the liver

list the three strategies to lower blood levels of cholesterol and which drug class correlates it

1. block the absorption of cholesterol from the diet into the bloodstream - ezetimibe

2. inhibit de novo synthesis of cholesterol - statin

3. block the recirculation of bile acids by increasing the removal of cholesterol by feces - bile acid sequestrants

what is the MOA for statins

strongly binds and inhibits HMG-CoA reductase

HMG-CoA reductase catalyzes the ___________ step in the synthesis of cholesterol

rate determining

what differs in the medicinal chemistry between a statin and the intermediate that HMG-CoA reductase is producing

statins have a C-C bond while the intermediate has a C-S bond

what two statins are considered prodrugs

simvastatin and lovastatin

what are the effects of HMG-CoA reductase inhibition

-decreased cholesterol synthesis

-increased production of HDLs

-increased number of LDL receptors

-increased clearance of LDL from the blood into the liver

what is the least potent statin

fluvastatin

what is the most potent statin

pitavastatin

what are special instructions for the lactone prodrug statins and why

take them at bedtime; cholesterol synthesis happens at night and they have a short half life

what statins have longer half lives

atorvastatin, pitavastatin, rosuvastatin, pravastatin, fluvastatin

what are the most common side effects from statins

SAMS - statin associated muscle symptoms

where do SAMS normally occur on the body

both sides of the body and on large muscle groups

when is there an increased risk of SAMS

when using vibrates or >1 g of niacin

SAMS usually occur within ___________of starting treatment

what is muscle soreness or tenderness

myalgia

what is muscle weakness paired with increased creatinine phosphokinase

myopathy

what is muscle inflammation

myositis

what is muscle breakdown

rhabdomyolysis

if there is muscle symptoms with a very high CPK and muscle protein in the urine

myoglobinuria and acute kidney failure

HMG-CoA creates the intermediate _________, which can eventually become ___________ or _____________

mevalonic acid, cholesterol, coenzyme Q10

an undesired effects of statins is that is decreases ____________ synthesis

coenzyme Q10

why is coenzyme Q10 important

essential for mitochondrial ATP production and decreased CoQ10 can impair muscle energy metabolism

besides CoQ10 disruption, how else do statins cause muscle damage

the decrease of cholesterol disrupts the muscle cell membrane integrity

do lipophilic or hydrophilic statins cause more muscle side effects

lipophilic

list the lipophilic statins

-simvastatin

-fluvastatin

-lovastatin

-atorvastatin

-pitavastatin

list the hydrophilic statins

pravastatin, rosuvastatin

why are lipophilic statins more prone to side effects

they can cross the cell membrane easier

what are the signs of liver damage in patients with statin use

passing brown or dark colored urine, feeling more tired, having jaundice

cholesterol lowering drugs should not be used if _______ or _______ is ______ times the upper limit of normal levels

AST, ALT, 3

grapefruit juice should not be taken when taking ________, _________ or __________

lovastatin, atorvastatin, simvastatin

what is the drug target for bempedoic acid

ATP citrate lyase

what is the MOA of bempedoic acid

inhibits cholesterol synthesis by inhibiting ACL (upstream of HMG-CoA reductase)

bempedoic acid causes ______ LDL reduction compared to statins

less

what can bempedoic acid be used for and why

an adjunct treatment if the patient cannot tolerate a statin, bempedoic acid is only active in the liver

bempedoic acid needs to be combined with __________ or _________ for high LDL reduction

ezetimibe, PCSK9 inhibitors

what is a side effect from bempedoic acid and why

increased gout risk because it prevents uric acid from being removed by the kidney

ezetimibe is a __________ that is converted to a ____________ metabolite that Is pharmacologically inactive

prodrug, glucuronide

normally, glucuronide metabolites are _________

inactive

MOA of ezetimibe

binds to and selectively blocks the function of NPC1L1, therefore inhibiting the absorption of dietary cholesterol in the blood

what are the outcomes of using ezetimibe

-low levels of cholesterol in the liver

-increased LDL receptors on the surface of the liver cells

-increased LDL clearance from the blood

ezetimibe targets _________ cholesterol

dietary

if ezetimibe is given alone, what can it increase

the activate of HMG-CoA reductase and therefore the de novo synthesis of cholesterol

what is the drug Vytorin composed of

ezetimibe and simvastatin

what two things can bile acids/salts do in the body

-emulsify lipids and vitamins A, D, E and K

-modulate blood cholesterol levels

what is the outcome of emulsification of lipids and vitamins

they are absorbed from the diet into the systemic bloodstream to be used by the body

cholesterol is metabolized to __________ which are 5% ____________ and 95% ____________

bile acids/bile salts, pooped out, returned to the circulation

what enzyme controls the metabolism of cholesterol to bempedoic aid

7-alpha- hydroxylase

how are bile acids a disguised form of cholesterol

they bind to 7-alpha hydroxylase and create a negative feedback mechanism, causing them to return to the liver where they were created

what two ways is cholesterol eliminated

through free cholesterol or disguised as a bile salt

bile acid sequestrants are not ________________and are therefore the safest for __________ patients

absorbed in the bloodstream, pregnant

why are bile acid sequestrants not able to be absorbed into the bloodstream

they are a solid polymer that is large and permanently charged and therefore cannot undergo passive diffusion or active transport

bile acid sequestrants MOA

soaks up negatively charged bile salts/bile acids and removes the negative feedback mechanism on 7-alpha-hydroxylase

what are the outcomes of using a bile acid sequestrant

increased LDL receptors and increase clearance of LDL from the blood

what are the disadvantages of using a bile acid sequestrant

-poor taste

-can increase TG levels

-can impair absorption of negatively charged drugs

-prevents vitamins A, D, E and K from being absorbed into the bloodstream

what is an important counseling point pertaining to bile acid sequestrants

take all other drugs 1-4 hours before or 4-6 hours after a BAS

what is a large drug interaction pertaining to bile acid sequestrants

ezetimibe, it decreases clinical efficacy of both drugs

what does PCSK9 do

attaches to LDL receptors and causes lysosomal degradation of the LDL receptor

what are the two drug strategies regarding PCSK9

-inhibit the formation of PCSK9 LDL receptor complex

-prevent the formation of PCSK9 itself

MOA of evolocumab and alirocumab

human monoclonal antibodies that bind to PCSK9 in the blood and prevents PCSK9 from attaching to LDL receptor on the surface of liver cells

what is inclisiran conjugated to

GalNAc

MOA of inclisiran

SiRNA that becomes part of a RNA-inducing silencing complex that binds to PCSK9 mRNA and degrades PCSK9

ROA of all PCSK9 inhibitors

SC injection

how often is inclisiran given

twice a year after loading doses

how often is evolocumab and alirocumab given

either every 2 weeks or monthly

MOA of fibrates

PPAR agonist

what is PPAR

nuclear transcription factor in the liver and skeletal muscles that controls free fatty acid metabolism

what are the effects of forming a vibrate-PPAR complex

-increases the expression of LDL

-Decreases the production of Apo-Ciii from the liver

-increases expression of Apo-Ai and Apo-Aii

-increases utilization of FFA as a source of energy

what does Apo-Ciii do

inhibits LPL and causes an increased clearance of TGs

what do Apo-Ai and Apo-Aii do

increases HDL production

fibrates drug interactions

-no gembfibrozil with other statins

-no gemfibrozil with ezetimibe

-no fibrates with bile acid sequestrants

why should gemfibrozil and statins not be combined

increases muscle toxicity by inhibiting DATP1B1 and statin glucuronidation

why should gemfibrozil and ezetimibe not be combined

decreases ezetimibe prodrug activation

why should fibrates not be combined with bile aid sequestrants

decreases absorption of fibrates into the blood

niacin is dosed up to _____ grams per day

6

niacin has the largest ________ increase out of any drug

HDL

MOA of niacin

GPR109A agonist in fat cells that inhibits lipolysis, wjocj releases FFA into the blood and liver

adverse effects of niacin

-hepatotoxicity

-flushing

what can be done to help flushing associated with niacin

take aspirin 30-60 minutes before niacin and take with food

what formulation of niacin causes the least possible side effects

ER

what formulations of niacin are the flushing risks high but hepatotoxicity is low

immediate release

what formulations of niacin are the flushing risks low but the hepatotoxicity risks is high

SR or CR

niacin drug interactions

-monitor for other hepatotoxic drugs

-take niacin 4-6 hours after taking a BAS

fish oils should be taken in adjunct to diet in patients with ______________

TG > 500 mg/dL

fish oils are __________ that need to be taken with __________

prodrugs, fat containing meal

MOA of fish oils

not well defined

when should fish oils be cautioned

patients who have an allergy to fish or shellfish

what does Lovaza consist of

EPA and DHA

DHA is linked to _________ LDL and ___________ side effects

increased, increased

Vascepa consists of _______ only

EPA

benefits of Vascepa

-high purity

-anti-inflammatory

-plaque stabilizing