Cardiology Test 1-Lapinsky- Lipid-modifying agents 2 (p29-48)

why should we care about bile salts?

1) bile acids and bile salts can act as __ __

anionic detergents

bile acids act as anionic detergents by ___ lipids and fat-soluble vitamins

emulsifying

what are the 4 fat soluble vitamins?

A, D, E, K

bile acids act as anionic detergents by emulsifying lipids and fat-soluble vitamins, which promotes ___ of these compounds from diet/intestines into bloodstream for use in body

absorption

which vitamin helps blood clot properly?

vitamin K

why should we care about bile salts?

2) bile acids modulate blood levels of __

cholesterol

Instead of using cholesterol for steroid production, the body can alternatively send it into the bile acid synthesis pathway to catabolize/break down cholesterol and facilitate its __ from the body

removal

the metabolism pathway that synthesizes bile acids/bile salts for removal of cholesterol is controlled by __ __-___

7 alpha-hydroxylase

7 α-hydroxylase catalyzes the __ __ step of the metabolism pathway to synthesize bile acids/bile salts for removal of cholesterol

rate determining

most of the bile acids/bile salts formed via 7 α-hydroxylase (about 95%) are ___ back into enterohepatic recirculation to be returned to liver

recycled

some of the bile acids/bile salts formed via 7 α-hydroxylase (about __%) are removed from body as feces

5

bile acids/bile salts can bind to 7 α-hydroxylase and exert a negative feedback ___ mechanism

inhibition

bile acids/bile salts can bind to 7 α-hydroxylase and exert a negative feedback inhibition mechanism. Bile Acid sequestrants (BAS) function to __ this negative feedback.

remove

once again, bile acids are needed to absorb lipids and fat-soluble vitamins from diet into the __

blood

bile acids are produced in the liver and then travel through the bile ducts with __ cholesterol and waste products in the small intestine

free

bile acids are then converted to bile __, which is then returned back to liver by enterohepatic recycling

salts

Cholesterol can be eliminated from body as either:

- __ cholesterol

- ___ as bile acid/bile salt

free, disguised

Bile acid sequestrants (BAS) are used to lower cholesterol blood levels and are NOT absorbed into systemic ___

bloodstream

since BAS are not absorbed into systemic bloodstream, they are some of the safest drugs in medicine for ___ patients

pregnant

in contrast to BAS, statins should be avoided in pregnant patients becuase they are ___

teratogenic

regardless of pH, a BAS is a solid polymer/"sand" that is large, insoluble, and permanently ___ charged

positively

since BAS is large, insoluble, and permanently positively charged, it __ undergo passive diffusion/active transport to enter systemic bloodstream

cannot

since BAS cannot undergo passive diffusion/active transport to enter systemic bloodstream, it tends to squat in the __ ___

GI tract

BAS tends to squat in the GI tract and soak up negatively charged bile acids/bile salts via numerous __ interactions

ionic

BAS soaking up bile acids/bile salts via numerous ionic interactions is how they remove the negative inhibition of bile acids/bile salts on __ __-___

7 alpha hydroxylase

since BAS removes the negative inhibition of bile acids/bile salts on 7 α-hydroxylase, this causes the liver to convert ___ cholesterol into bile acids/bile salts

more

since BAS removes the negative inhibition of bile acids/bile salts on 7 α-hydroxylase, this causes the liver to convert more cholesterol into bile acids/bile salts, which leads to ___ LDL receptors that clear LDL from blood

increased

BAS strengths

1) safe in pregnancy and ___

2) no systemic absorption

3) useful for __ intolerance

pediatrics, statin

BAS limitations

1) poor patient ___/taste

2) some BAS can __ triglyceride levels

tolerability, increase

BAS limitations

3) can impair oral absorption of __ charged drugs

negatively

Statins strengths

1) most ___ at LDL lowering

2) proven cardiovascular outcome benefit

effective

Statins limitations

1) muscle and liver side effects

2) NOT suitable in ___

pregnancy

Ezetimibe strengths

1) add-on therapy

2) ___ side effects

3) safe for __ intolerance

minimal, statin

Ezetimibe limitations

1) modest effect alone

2) outcome benefit only in __

combination

Bempedoic acid strengths

1) no __ toxicity

2) helpful for statin intolerance

muscle

Bempedoic acid limitations

1) __ risk

2) cost

3) ___ pediatric or pregnancy use

gout, no

___ drug interactions: one drug changes the absorption, distribution, metabolism, or excretion of another drug... leading to altered drug levels in the body

pharmacokinetic

___ drug interactions: two or more drugs act at the same or related drug targets, leading to additive, synergistic, or antagonistic effects

pharmacodynamic

___ (physicochemical) drug interactions: drugs or solutions interact before administration to patient (usually a compounding/IV compatibility issue

pharmaceutical

BAS will impair oral absorption of:

1) any ___ charged drug that requires oral absorption into the bloodstream for desired drug action

negatively

BAS will impair oral absorption of:

2) fat-soluble ___ A, D, E and K

vitamins

BAS impairs oral absorption of fat-soluble vitamins. This means the drug could lead to undesirable ___ via lower production of blood clotting factors that require vitamin k for their synthesis

bleeding

traditional patient counseling for a BAS includes ___ doses!!!

separate

using Ezetimibe and BAS together will __ the efficacy of BOTH drugs

decrease

using Ezetimibe and BAS together will decrease the efficacy of BOTH drugs because they will __ to each other, thus making BAS unable to soak up bile acids/bile salts and making Ezetimibe unable to block cholesterol absorption

bind

patient counseling note: take Ezetimibe either __ hours before or __ hours after taking a BAS

2, 4

proprotein convertase subtilisin/Kexin Type 9 (____) is an enzyme that binds to LDL receptors

PCSK9

PCSK9 causes __ ___ of LDL receptors, thus increasing the amount of LDL in the blood (bad)

lysosomal degredation

___: an organelle that functions as a "degredation center" for catabolic degredation of proteins, polysaccharides, and lipids

lysosome

we want to ____ PCSK9 so there is increased clearance of LDL from the blood into the liver, therefore lowering LDL levels in blood

inhibit

2 ways we can inhibit PCSK9

1) inhibit formation of PCSK9 ___

2) inhibit PCSK9 from binding to __ __

itself, LDL receptors

to inhibit PCSK9 from binding to LDL receptors, we use ___ (Repatha) and ___ (Praluent)

evolocumab, alirocumab

Evolocumab and alirocumab bind to PCSK9 in the ___, which prevents it from attaching to LDL receptors and degrading them, which increases LDL clearance

blood

to inhibit formation of PCSK9 itself, we use ___ (leqvio)

inclisiran

Inclisiran (Leqvio) is a small interfering RNA (___) drug

siRNA

Inclisiran (Leqvio) is a siRNA drug that is chemically modified and conjugated to GaINAc for targeted delivery to hepatocytes via the ___ receptor

asialoglycoprotein

How Inclisiran works:

1) GaINAc directs inclisiran into liver cell

2) inside liver cell, inclisiran becomes part of the RNA-inducing silencing complex (___)

RISC

How Inclisiran works:

3) the RISC then uses Inclisiran to bind to PCSK9 RNA

4) PCSK9 RNA is degraded, so __ PCSK9 is produced

5) less PCSK9= more clearance of LDL

less

unlike Inclisiran (which is siRNA), Evolocumab and Alirocumab are fully human monoclonal ____ (mAbs)

antibodies

antibodies are large y shaped proteins that require ___ administration and are catabolized to amino acids

parenteral

the mABs (Evolocumab and Alirocumab) as well as Inclisiran route of administration= ___ injection

subcutaneous

Inclisiran is dosed only __ yearly after initial loading

twice

there are no oral formulations of the mABs (Evolocumab and Alirocumab) or Inclisiran due to the molecular __ and susceptibility to GI ___ of these drugs

size, degredation

elimination half life of evolucumab is 11-17 days, and of alirocumab is 17-20 days, but Inclisiran is effective at LDL lowering for about __ months after dosing

6

mABs are proteolytically catabolized to amino acids, and have __ significant drug interactions with statins, Ezetimibe, or other common lipid-lowering therapies

no

statins can undesirably __ PCSK9 expression

upregulate

statins can undesirably upregulate PCSK9 expression, therefore PCSK9 inhibitors (Evolocumab, Alirocumab, Inclisiran) can be used to ____ this upregulation

counteract

Fibrate= ___

phenoxyisobutyrate

Fibrates are primarily __ lowering drugs, but also increase HDL

triglyceride

Fibrates are PPAR-α ___

agonists

PPAR-α is a nuclear transcription factor mainly expressed in the __, skeletal ___, heart, and kidney

liver, muscle

Fibrates lower TG becuase when they agonize PPAR-α, this causes increased transcription of genes that control __ __ __ (FFA) metabolism

free fatty acid

high blood levels of TG increases the risk of __

pancreatitis

TGs are biochemically important as a storage form of __

energy

4 effects of forming a Fibrate- PPAR-α complex:

1) fibrates can increase the expression of __ ___ (LPL)

lipoprotein lipase

lipoprotein lipase (LPL) hydrolyzes ___ into glycerol and FFA

triglycerides

fibrates increasing LPL expression, ie accelerating the hydrolysis of TGs --> FFAs enables the FFAs to enter tissues for ____

utilization

4 effects of forming a Fibrate- PPAR-α complex:

2) fibrates can __ production of apolipoprotein C-III by the liver

decrease

apolipoprotein C-III is an __ of LPL

inhibitor

since fibrates decrease production of apolipoprotein C-III (which inhibits LPL), fibrates will ultimately cause ___ clearance of triglycerides

increased

4 effects of forming a Fibrate- PPAR-α complex:

3) fibrates can ___ the expression of apolipoprotein A-I and apolipoprotein A-II

increase

apolipoprotein A-I and apolipoprotiein A-II are major protein components of __

HDL

by increasing expression of apolipoprotein A-I and apolipoprotein A-II, fibrates are increasing production of ___

HDL

4 effects of forming a Fibrate- PPAR-α complex:

4) within liver and muscle cells, fibrates can ___ oxygen use and FFA utilization as a source of energy

increase

fibrates increasing oxygen use and FFA utilization causes less FFAs to be available that could be used to synthesize ____

triglycerides

most guidelines say NOT to use which fibrate concurrently with any statin or Ezetimibe?

gemfibrozil

you should not use gemfibrozil concurrently with any statin because it undesirably increases statin ___ toxicity

muscle

gemfibrozil increases statin muscle toxicity by:

1) inhibiting ___ (transporter that moves statins from blood to liver)

OATP1B1

gemfibrozil increases statin muscle toxicity by:

2) inhibiting statin ___ (process that inactivates statins)

glucuronidation

you should not use gemfibrozil with ezetimibe because it undesirably ____ ezetimibe prodrug activation

decreases

to solve increased muscle toxicity from using gemfibrozil+statin and decreased prodrug activation from using gemfibrozil+ ezetimibe, you can use _____ instead of gemfibrozil

fenofibrate

you should not use any fibrate with a ___ because it decreases absorption of fibrate into the blood

BAS

another drug used to treat lipid disorders is __, also known as nicotinic acid or vitamin B3

niacin

when used to treat lipid disorders, Niacin is dosed up to __ grams per day

6

Lipid effects of Niacin

-decrease ___ by 20-50%

-increase ___ by 15-35%

-decreases LDL by 5-25%

triglycerides, HDL

of ANY drug niacin has the __ HDL increase

largest

there is extended release formulations of niacin because the half-life is only 1 hour, and therefore would otherwise require ___ dosings

multiple

Niacin's primary site of drug action is in ___ (fat cells)

adipocytes

Niacin MOA:

step 1) Niacin is GPCR109 ___

step 2) Niacin-GPCR109 complex inhibits __

step 3) this causes less FFAs released into blood

agonist, lipolysis

Niacin causes less FFAs released into blood by agonizing GPR109A. The liver responds by ___ synthesis of TGs and VLDL

decreasing