Cardiology Test 1-Lapinsky- Lipid-modifying agents 1 (p1-28)

Cholesterol is an important structural component of ___ ___

cell membranes

Cholesterol is the starting material to synthesize ___ hormones

steroid

Cholesterol is the starting material to synthesize steroid hormones like glucocorticoids, which suppress ___

inflammation

Cholesterol is the starting material to synthesize steroid hormones like mineralocorticoids (eg aldosterone), which control __ __

blood pressure

Cholesterol is also the starting material to synthesize __ __

bile acids

Bile acids/bile salts play a key role in the digestion/absorption of __ and fat-soluble vitamins (from the diet) in the small intestine

fats

the bile acid cycle, also called enterohepatic circulation, involves bile acids being ___ into the ileum, returning to the liver via the portal vein, and being re-secreted into bile

reabsorbed

Bile acids help regulate ___ blood levels!

cholesterol

Bile acids help regulate cholesterol blood levels! namely by promoting the breakdown of cholesterol, which is eliminates from the body either as free __ or as __ __

cholesterol, bile acid

5% of bile salts are __ in the feces-- this is cholesterol disguised as a bile salt

lost

elevated blood levels of cholesterol increase risk of ____ (formation of plaque in arteries)

atherosclerosis

atherosclerosis is asymptomatic, but leads to ASCVD, which includes:

1) myocardial infarction (heart attack)

2) stroke

3) ___ ischemic attack (mini stroke)

transient

atherosclerosis is asymptomatic, but leads to ASCVD, which includes:

4) stable ___

5) peripheral artery disease

angina

2 main sources of cholesterol

1) our __

2) de novo/from scratch biosynthesis of cholesterol in the ___ by hepatocytes

diet, liver

How can we lower blood levels of cholesterol?

1) block absorption of cholesterol from diet into the blood stream by using ___

ezetimibe

How can we lower blood levels of cholesterol?

2) inhibit de novo synthesis of cholesterol by using __

statins

How can we lower blood levels of cholesterol?

3) block the enterohepatic circulation of bile acids to increase removal of cholesterol by using ____ ___ ___ (BAS)

bile acid sequestrants

VLDL are composed primarily of ____ and ultimately become LDL

triglycerides

LDL (bad cholesterol) are the number one driver of ___

atherosclerosis

HDL (good cholesterol) removes excess ___ from the tissues and arteries and returns it to liver for disposal

cholesterol

statins are grouped by ___ based on their LDL-lowering ability. Patients are categorized into statin benefit groups to determine the appropriate statin intensity

intensity

what is the enzyme that catalyzes the rate-limiting step in synthesis of cholesterol?

HMG CoA reductase

statins bind tightly to, and strongly ___ HMG-CoA reductase

inhibit

HMG-CoA reductase normally breaks the carbon-___ bond in the synthesis of cholesterol

sulfur

all HMG-CoA reductase inhibitors (including statins) are able inhibit the enzyme because their carbon-___ bond cannot be broken

carbon

statins all have an ionized ___ ___

carboxylic acid

Prodrugs are not active inhibitors of HMG CoA reductase until their lactone ring undergos in vivo hydrolysis to ionize the carboxylic acid. What statins are prodrugs?

lovastatin, simvastatin

the ionized carboxylic acid on statins forms a key __ anchoring interaction with positively charged ions within the active site of HMG CoA reductase

ionic

in addition to inhibiting cholesterol synthesis, statins will upregulate the number of ___ ___ on hepatocytes

LDL receptors

statins upregulate the number of LDL receptors on hepatocytes, which ultimately increases ___ of LDL from the blood into the liver

clearance

what are the statins going from most potent--> least potent (pharmacists rock at saving lives and preventing flu)

pitavastatin, rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin

since simvastatin and lovastatin are lactone prodrugs, they have very ___ half lives

short

due to the short half-lives of simvastatin and lovastatin, they should be taken at ___ because maximum de novo cholesterol synthesis happens between 12Am-2Am

bedtime

pitavastatin, rosuvastatin, atorvastatin, pravastatin, fluvastatin are active HMG-CoA reductase inhibitors (ie not prodrugs) and have ___ half lives

longer

in general, the statins with longer half lives can be taken at __ time of day

any

important patient counseling for statins includes describing symptoms of ___ __ (#1 adverse effect)

muscle damage

What does SAMS stand for?

statin associated muscle symptoms

SAMS usually presents as muscle soreness, tiredness, or weakness that is ___ (on both sides of body) in __ muscle groups (legs, back, arms)

symmetrical, large

SAMS can develop at ANY time during statin use, but are usually within __ weeks of starting treatment

6

there is increased risk of muscle effects with statins when used with

1) ____

2) more than 1g of __

fibrates, niacin

what is the term for muscle soreness and tenderness?

myalgia

___ ___ (CPK): a marker of damage of creatinine kinase-rich tissue, such as heart muscle tissue in myocardial infarction

creatinine phosphokinase

what is the term for muscle weakness with or without increased CPK?

myopathy

what is the term for muscle inflammation?

myositis

what is the term for the most severe muscle effect of statins, which includes muscle symptoms, very high CPK, and muscle protein in the urine?

rhabdomyolysis

___= muscle protein in the urine, which can lead to acute kidney/renal failure

myoglobulinuria

HMG CoA reductase inhibition via a statin within the liver/hepatocytes is desired or undesired?

desired

HMG CoA reductase inhibition via a statin within the muscle/myocytes is desired or undesired?

undesired

2 ways statins notoriously cause muscle damage:

1) __ coenzyme Q10 synthesis

2) disruption of muscle __ ___ integrity

decreased, cell membrane

in muscle cells, coenzyme q10 (ubiquinone) is crucial for mitochondrial __ production

ATP

Using a statin decreases coenzyme q10 synthesis, which may impair muscle __ metabolism concerning muscle cells, leading to muscle weakness, pain, and fatigue

energy

patients may __ with OTC CoQ10 to help with muscle side effects

supplement

since cholesterol is an essential component of cell membranes, reducing cholesterol via statin use will lead to muscle cell membrane ___

instability

Muscle cell membrane instability due to lower cholesterol from statin use increases the susceptibility of these muscle cells to mechanical stress, injury, and __

breakdown

___: predicted value that estimates how lipophilic or hydrophilic a given compound is

cLogP

What are the 2 hydrophilic statins?

pravastatin and rosuvastatin

simvastatin, fluvastatin, lovastatin, atorvastatin, and pitavastatin are hydrophilic or lipophilic?

lipophilic

what is most lipid soluble statin?

simvastatin

compared to hydrophilic statins, lipophilic statins can more easily cross cell membranes via passive diffusion to reach __-__ tissues and the __

non-hepatic, CNS

since lipophilic statins can more easily reach non-hepatic tissues, there is a greater risk for __

SAMS

since lipophilic statins can more easily reach CNS, there is a greater risk for:

1)__ impairment

2)disturbed ___

cognitive, sleep

what is the most hydrophilic statin?

rosuvastatin

hydrophilic statins (pravastatin and rosuvastatin) are more liver/hepato- ___

selective

hydrophilic statins (pravastatin and rosuvastatin) are more liver/hepato- selective and therefore have __ risk for muscle and CNS side effects

decreased

patient counseling for statins should include watching for symptoms of __ damage (passing dark urine, yellow skin/white of eyes)

liver

statins are contraindicated in patients with active __ disease

liver

Many cholesterol-lowering drugs can cause liver damage. These drugs should not be used if the AST or ALT is more than __x the upper limit of normal

3

__ __ __ (LFTs) should be monitored during statin treatment

liver function tests

patient counseling for statins should include warning to not consume __ products while on lovastatin, atorvastatin, or simvastatin because they can cause statin toxicity

grapefruit

patients should not consume grapefruit when taking lovastatin, atorvastatin, or simvastatin because these statins rely heavily on ___ for their natural drug inactivation metabolism

CYP3A4

statins are contraindicated with use of strong ___ inhibitors:

-grapefruit juice

-azole antifungals

-macrolide antibiotics (erythromycin, clarithromycin)

CYP3A4

chemicals (most likely __) in grapefruit products lower the activity of enzymes that break down lovastatin, atorvastatin, or simvastatin, which causes more of the medication to be in the patient's bloodstream

flavonoids

hepatocytes/liver cells respond to low levels of cholesterol by upregulating __ ___, which facilitates the desired uptake and removal or undesired LDL cholesterol from the blood

LDL receptors

another established drug target concerning the cholesterol biosynthesis pathway in hepatocytes is __ ___ ___(ACL)

ATP citrate lyase

What is the other name for ETC-1002, which is a prodrug that inhibits ACL to reduce cholesterol synthesis

bempedoic acid

bempedoic acid is an ATP citrate lyase inhibitor, this drug target is ___ of HMG coA reductase (which is inhibited by statins)

upstream

the physiological effect of bempedoic acid and statins are the same. They both decrease cholesterol synthesis, increase LDL receptors, and increase LDL ___

clearance

is bempedoic acid or statins more effective at reducing LDL-C?

statins

statins are active in both __ and __

liver, muscle

bempedoic acid is active only in __

liver

bempedoic acid is considered __ because since there is no acyl-coA synthetase for prodrug activation in muscle cells, it does not cause the muscle side effects that statins do

safer

is bempedoic acid or statins first line?

statins

bempedoic acid is mainly used as an adjunct, but is useful alternative for patients who are statin __

intolerant

bempedoic acid may prevent uric acid from being removed from kidney, which increases risk for __

gout

statins alone often suffice to reduce high LDL, but you often need to combine bempedoic acid with __ or __ __

ezetimibe, PCSK9 inhibitors

Ezetimibe is a unique prodrug, it is converted in the intestinal wall and liver to a pharmacological active _____ ___

glucuronide metabolite

Ezetimibe is highly unusual, because in the body, most glucuronide metabolites are pharmacologically ___

inactive

glucuronidation is one specific process commonly associated with phase II natural drug ___ metabolism ("conjugation")

inactivation

Ezetimibe MOA: binds to and selectively blocks function of __ in small intestine

NPC1L1

Ezetimibe MOA: binds to and selectively blocks function of NPC1L1 in small intestine, thus preventing ___ of dietary cholesterol into the blood, which causes decreased delivery of cholesterol to liver

absorption

the low levels of cholesterol in liver from Ezetimibe leads to upregulation of LDL receptors, which facilitates increased ___ of LDL from the blood

clearance

Statins vs Ezetimibe

Statins target cholesterol ___

Ezetimibe targets ___ cholesterol

synthesis, dietary

if given alone, Ezetimibe can cause an undesirable stimulation of de novo synthesis of cholesterol in liver by increasing activity of __ __ __

HMG coA reductase

to address the undesirable stimulation of cholesterol synthesis by giving Ezetimibe alone, the drug ___ combines ezetimibe with simvastatin

vytorin