Pharmacology - Dyslipidemia Part 2 Flashcards
2 lipid lowering agents (not statins) that interact with statins to increase the risk of myopathy
gemfibrozil
niacin
atorvastatin + digoxin interaction
digoxin toxicity - levels increased by 20%
statin + grapefruit juice
grapefruit inhibits CYP3A4 - increased statin levels and potential myopathy
dr prescribes atorvastatin + cyclosporine
what is recommendation
what if it’s another drug that reacts
do not go over 10mg of atorvastatin QD
use caution when going over 20mg of atorvastatin – lowest dose should be used
statin + resin counseling points
statin should be given at least 1 hour before the resin
if pt already took the resin, have to wait AL LEAST 4 HOURS before taking the statin
this is bc the absorption of the statin will decrease
true or false
pravastatin is not a prodrug
true
pravastatin is CI with what gout agent
colchicine
when giving rosuvastatin with ___ or ___, low doses of rosuvastatin should be used due to risk of myopathy
gemfibrozil and cyclosporine
in general, if fibrates are given with a statin, which fibrate is preferred bc it has less risk of causing myopathy?
fenofibrate over gemfibrozil
for which statin are polymorphisms in CYP2C19 a concern
rosuvastatin
if pts have low activity of the enzyme, they have higher risk of myopathy and liver damage
a patient with _____ may be predisposed to rhabdomyolysis from statins
renal failure
what do statins do to INR
increase INR – bleeding risk for warfarin. time to clot is increased
statins increase or decrease transaminases?
increase
true or false
chronic alcohol drinkers can take statins
not really – too much hepatotoxicity
which group of people are predisposed to myopathy from rosuvastatin and why
japanese and chinese bc of CYP2C19 polymorphisms
proteinuria when taking statins can be a sign of….
muscle damage, kidney damage
(rhabdomyolysis damages the kidney)
pitavastatin is contraindicated with ___ and ____
fibrates and cyclosporine
advantage of pitavastatin over other statins
does not affect warfarin! no increased bleeding risk
name 3 bile acid-binding resins
colestipol
cholestyramine
colesevelam
bile acid-binding resins are a _____-exchange copolymer
ANION EXCHANGE
Do bile acid-binding resin drugs get absorbed?
NO - they are too large
they dont need to be absorbed to do their mechanism. they work in the GI tract and then get excreted through the feces, bound to the bile acid
in what organ is bile acid made?
in what organ is bile acid stored?
made in the liver, stored in the gallbladder
what is the major, endogenous role of bile acids?
they emulsify the fat that we eat and convert it to chylomicrons
explain the MOA of bile acid-binding resins
they go into the GI tract where they bind bile acids. (bc the resins are highly positively charged and the bile acids themselves are highly NEGATIVELY charged)
these bile acids can no longer be reabsorbed into the body through enterohepatic circulation
instead, the bile acid resin + the bile acid go through the hepatic portal vein, get converted to bile, and eventually excreted through the feces
the liver responds to less bile acids in the body by making more bile acids with lipids. to do this, more LDL receptors are produced and LDL is taken from the blood – and therefore LDL goes down!
bile acid resins vs bile acids
which have a positive charge and which have a negative charge?
bile acids have a negative charge and resins have a positive charge
true or false
bile acid resins can be used as monotherapy
true - or with statins
true or false
bile acid-binding resins increase triglyceride synthesis by the liver
true
therefore, contraindicated in severe hypertriglyceriedemia!!! can cause pancreatitis
what is an advantage of using bile acid-binding resins with statins
the dose of each can be reduced - less prone ot statin side effects
when are bile acid resins taken
at breakfast or dinner
remember - if pt taking statin - need to take at least an hour before resin, or at least 4 hours after
which 2 bile acid resins come as a powder in which the patient has to make a slurry and have it as a juice?
which comes as a tablet?
powder - cholestyramine, colestipol
tab - colesevelam
true or false
bile acid resins are generally well tolerated
true
due to chloride salts, there are rare cases of hyperchloremic acidosis
bile acid resins are contraindicated if patients have high levels of ___
triglcyerides!!
bc the resins increase synthesis of TG
CI bc too much TG can cause pancreatitis
bile acid resins can cause malabsorption of ____
vitamin K
bc it will be removed with the bile acid. it’s a fat soluble vitamin
name some potential side effects of bile acid resins
heartburn (bc acidic)
malabsorption of vitamin k
bloating
dyspepsia
constipation
true or false
bile acid resins are contraindicated in diverticulitis
true
these 2 bile acid resins bind and interfere with the absorption of many drugs
name some of them
cholestyramine and colestipol
thiazides, furosemide, propranolol, levothyroxine, digoxin, warfarin, some statins (BC ACIDIC!!!!)
TRUE OR FALSE
acidic drugs are contraindicated with bile acid resins
FALSE
not contraindicated, just not given at the same time because the drug will bind the resin and not be absorbed
of the 2 fibrates, which is a prodrug
fenfibrate
which fibrate is mostly excreted unchanged?
explain the metabolism of the other fibrate
unchanged - gemfibrozil
glucuronidation - fenofibrate
which fibrate is highly protein bound, undergoes enterhepatic circulation, and readily passes the placenta
gemfibrozil
what happens when PPAR-a is activated?
WHEN is it activated? explain
WHAT DRUGS ARE PPAR-A AGONISTS??
fatty acid oxidation is induced
activated in times of fasting
the fatty acids are broken down and used for energy - maintain blood sugar
the fibrates
explain how fibrates affect these activities in the liver:
-Apoprotein synthesis
-Triglyceride secretion and synthesis
-fatty acids
increase “good” apoprotein synthesis (I and II)
decreased bad apoprotein synthesis (III)
decreased synthesis and secretion of TG
increased fatty acid oxidation
what class of receptor is PPAR-a
nuclear receptor
true or false
fibrates decrease fatty acid oxidation
FALSE - increase
true or false
fibrates increase the synthesis of lipoprotein lipase
true
which fibrate is more effective at increasing HDL levels?
fenofibrate
is apoprotein CIII good or bad and why
bad - inhibits lipolysis
how do fibrates affect thrombosis?
they have antithrombotic effects – inhibit clotting, and enhance the fibrinolysis of clots
***true or false
fibrates have very little effect on LDL cholesterol
TRUE
really only decrease triglycerides
fibrates are useful drugs in hypertriglyceridemias in which ____ predominates
VLDL
(has very high triglyceride content. only chylomicrons have higher)
5 potential AE of fibrates
liver toxicity, rashes, myopathy
cholesterol gallstones, pancreatitis
the risk of myopathy from fibrates ALONE is pretty rare. however, this risk increases when…
combined with a reductase inhibitor (statin)
DDI concern with fibrates
potentiation of warfarin - bleeding risk
true or false
fibrates react with alcohol
true - increased risk of necrotizing myopathy
**general mechanism of ezetimibe
inhibits intestinal absorption of sterols (ie - cholesterol)
does this by inhibiting NPC1L1, a transport protein that uptakes cholesterol into the intestines
explain the synergy effect of zetia + statin
bc zetia reduces cholesterol absorption by 50%, there is a compensatory increase in cholesterol synthesis in the liver.
HOWEVER, statins inhibit this cholesterol synthesis!!!
the 2 different MOA’s work together to significantly decrease LDL
true or false
because the mechanism of zetia is to decrease the absorption of dietary cholesterol, it is NOT effective against cholesterol that is endogenously produced
FALSE - it still is, bc it inhibits the reabsorption of cholesterol into the bile
*true or false
ezetimibe is a non-competitive inhibitor. it does NOT compete with sterols
true
binds an allosteric site - not the same site
true or false
zetia can be given with bile acid resins
FALSE - CONTRAINDICATED
the absorption of ezetimibe will be inhibited
metabolism of ezetimibe
water insoluble - so gets metabolized
glcuronidation
how is zetia mainly excreted
in feces
zetia + fibrates
the concentration of ezetimibe in the plasma will be increased
ezetimibe is only used as monotherapy in what scenario
in patients intolerant to statins
zetia is particularly useful in which disease?
phytosterolemia ( too many plant sterols)
true or false
zetia is generally well tolerated
true
name 2 PCSK9 antibodies used for dyslipidemia
evolocumab (repatha)
alirocumab (praluent)
explain the MOA of PCSK9 antibodies to lower cholesterol
in the presence of PCSK9, the endosome with PCSK9 + receptor + LDL cholesterol, ALL BREAKS DOWN, so there is very little LDL receptor cycling back to the surface of the hepatocyte. this means that there is LESS LDL CHOLESTEROL BINDING TO LDL RECPETORS – resulting in less elimination and ultimately higher levels in the blood
HOWEVER, PCSK9 antibodies bind PCKS9 protease and PREVENT it from going into the endosome and degrading the receptor. instead, ONLY the LDL particle is destroyed, and the receptor is recycled back to the surface to take in and ELIMINATE MORE LDL cholesterol
explain the synergy of statins + PCSK9 inhibitors
statins upregulate the production of LDL receptors, while at the same time PCKS9 inhibitors prevent these new receptors’ destruction
PCSK9 is a ____ that binds to ____ on the surface of ____ and enhances ____
what is the result
protease that binds LDL receptor on the surface of hepatocytes
this enhances the lysosomal degradation of the LDL receptor which is BAD because less LDL will be eliminated so LDL plasma concentrations will be higher
true or false
the PCSK9 inhibitors increase LDL receptor concentration
true!! these receptors enhance the elimination of LDL through the liver
route of administration of PCSK9 inhibitors
subq injection either q 2 weeks or monthly
true or false
there are NO myopathy issues with PCSK9 inhibitors
true
Niacin is the component of…
vitamin B3
in general, niacin decreases what 3 things
triglycerides
LDL production
VLDL secretion (from the liver)
what does niacin increase
HDL
dose of niacin to have positive effects on LDL and HDL
need very high dose
true or false
niacin is excreted unchanged
true
or only the major metabolite - nicotinuric acid is found in urine
***2 places in the body where niacin acts
adipose (fat) tissue
the liver
explain the MOA of niacin in adipose tissue
INHIBITS the lipolysis of triglycerides
decreases number of free fatty acids sent to liver, thus decreasing triglyceride synthesis
explain the MOA of niacin in the liver
inhibits synthesis and esterification of fatty acids
decreased VLDL production and TG synthesis
decreased LDL
true or false
niacin enhances LPL activity
true
true or false
niacin decreases HDL levels
FALSE - raises
niacin is indicated for…
hypertriglyceridemia
high LDL-c
true or false
niacin can be used in combo with a statin or a resin
true
*true or false
niacin only affects LDL levels
FALSE
also decreases triglycerides
rare AE of niacin. if it occurs, must be discontinued
arrhythmias
3 AE niacin (besides arrhythmia)
flushing
dyspepsia
hepatoxicity
fish oil is only used for….
reducing VLDL triglycerices
adjunct to diet in patients with severe hypertriglyceridemia
proposed MOA of fish oil
not really well known - but thought to act on PPAR-a (like fibrates)
when is prescription strength fish oil given
for pancreatitis – triglycerides higher than 1000
bempedoic acid is a ___ inhibitor
ATP citrate lyase
what is the ATP citrate lyase enzyme
an enzyme that is upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway
How does bempedoic acid decrease LDL
inhibits ATP citrate lyase - an enzyme in the cholesteorl synthesis pathway
AE of bempedoic acid
hyperuricemia (gout!)
tendon rupture
muscle pain
counsel to watch for joint pain!
what is inclisiran and when is it used
a siRNA (small interfering RNA) that is directed at inhibiting PCSK9 mRNA
as adjunct to diet and to high dose statin therapy
