1-6 and 7 Flashcards
What type of patient should NOT be prescribed resins (bile acid sequestrants)?
Patient with severe hypertriglyceridemia
There is a DDI between resins and what three other drug classes?
Beta blockers, Loop Diuretics, and Thiazide Diuretics
What drug class works via charge based interaction?
Bile Acid Sequestrants
Bile acid sequestrants are ___ charged while bile acids are ___ charged. Given this, bile-resin complex is eliminated from body via stool.
Bile acid sequestrants are positively charged
Bile acids are negatively charged
What compensation occurs due to bile acid sequestrants?
-Increase in LDL receptors
What are the three bile acid sequestrants?
(coles in a pool, cole saved a lamb, coles tyrin me out)
1) Colesevelam
2) Colestipol
3) Cholestyramine
True or False: Depletion of bile acid is accompanied by a decrease in new bile acid synthesis in the liver
False - Depletion of bile acid is accompanied by an INCREASE in new bile acid synthesis in the liver
How does increasing bile synthesis affect hepatic cholesterol content?
Increasing bile synthesis DECREASES hepatic cholesterol content
True or False: Colestipol increases hepatic LDL receptor membrane localization and enhances LDL clearance from circulation
True
Simvastatin and Atrorvastatin belong to which drug class?
Statins (HMG-CoA Reductase inhibitors)
True or False: Simvastatin and Lovastatin are inactive lactones that need to be converted to active forms
True -
Their active forms are simvastatin hydroxy acid and lovastatin hydrox acid
Which drug class has extensive first pass metabolism and is regulated by OATP1B1?
Statins (HMG-CoA Reductase Inhibitors)
Why is myopathy an AE of statins?
Statins can induce reduction in CoQ10 synthesis
Rhabdomyolysis (rapid muscle damage) is an AE associated with which drug class?
What increases one’s risk of developing this?
Statins
Consuming grapefruit (furanocoumarins in grapefruit inhibits CYP, preventing statin metabolism, increasing systemic presence and leading to toxicity)
True or False: statins have role in anti-inflammatio/anti-coagulation, decreasing LDL-C levels, and improving endothelial function
True
Inhibition of HMG CoA results in increased expression of which gene?
LDL receptor gene
Statins cause reduced synthesis of cholesterol within cells. As a result of this, __ proteins (found in ER and Golgi) are cleaved by ___, leading proteins to be translocated into the nucleus.
SREBP (sterol responsive element binding protein)
Site Proteases (S1P, S2P)
How does the presence of SREBP in the nucleus affect LDL receptor gene?
Leads to increase in LDL receptor genes, thereby causing more LDL receptors on surface of cell, which aid in removing LDL cholesterol from blood
Prior to being secreted into the plasma, where is Apo-A1 made?
Liver
When ApoA-I and phospholipid interact with each other (via RCT), they form what two HDL molecules?
1) Nascent HDL (Pre-B1-HDL)
2) Nascent Discoidal HDL (ndHDL)
In reverse cholesterol transport, cholesterol is effluxed by receptors like ___, ___, or ___
ABCA1, ABCG1, SR-B1
In reverse cholesterol transport, the nascent HDL absorbs free cholesterol in circulation and converts them to cholesterol esters via ____, and enzyme.
LCAT (lectin-cholesterol acetyltransferase)
As nascent LDH accumulates more cholesterol ester, it grows in sizes and matures, becoming ___ and ___ particles (also known as a1-4 particles)
HDL 3 and HDL 2 particles
Which enzyme is the rate limiting one involved in the step of Reverse Cholesterol Transport whereby HDL size increases?
PLTP (Phospholipid transfer protein)
LCAT converts pre-B-1 (nascent LDH) to ___
PLTP converts HDL3 to ___
HDL3; HDL2
True or False: As ApoA1 containing particles mature, they try to intake as many TG particles as possible
True
Which protein helps in the exchange of cholesterol ester (CE) and triglyceride particles (TG) between HDL and ApoB100 (VLDL and LDL) containing lipoprotein particles?
CETP (cholesterol ester transfer protein)
Once cholesterol esters are taken up by VLDL and LDL, they are transferred back to the liver via ___ receptor. Cholesterol esters will be broken down and made to make bile.
LDL - receptor
____: pathway that transports cholesterol from extrahepatic tissues (vessel wall) to the liver and intestines for recycling and excretion
Reverse Cholesterol Transfer
What are the two principal mediators for reverse cholesterol transport?
HDL (high density lipoprotein)
ApoA-I (the apoprotein associated with HDL)
True or False: HDL levels in body can help assess efficiency of RCT and cholesterol efflux out of vessel walls
True
True or False: LDL is primarily involved with removing cholesterol from atherosclerotic plaques, back into the liver, and finally into bile
False - primarily mediated by HDL
Why is HDL considered ‘good’ cholesterol?
Why is LDL considered ‘bad’ cholesterol?
HDL: REMOVES cholesterol from blood/artery walls
LDL: DEPOSITS cholesterol between layers in artery wall and STARTS process of atherosclerosis
_____is formed by bridging of Apo B 100 (containing LDL) and Apo A via: disulfide bond and is a NOVEL BIOMARKER FOR CV DISEASE AND ATHEROSCLEROSIS
Lipoprotein (a)
(levels greater than 75 nmol/L are considered risk factors)
What gene mutation can lead to hyperlipidemia?
Mutation in LPL (lipoprotein lipase) in infancy or childhood
HDL is a ___ containing lipoprotein
Apo A
Liver derived VLDL and LDL lipoproteins are ____ containing lipoproteins
Apo B-100
Diet or gut derived lipoproteins are chylomicron ______ containing lipoproteins
Apo B-48
What happens if apoprotein (acts as ligand) is not located on lipoprotein surface, as it normally is?
Particles are not taken up by liver
What is found within a lipoprotein?
1) Triglycerides
2) Cholesterol esters
What is found on surface of lipoprotein?
1) Apoprotein
2) Cholesterol
Chylomicrons are lipoproteins formed in the ____ following dietary fat intake
intestine
VLDL is the lipoprotein produced from the __
liver
True or False: Both VLDL and chylomicrons contain triglycerides that undergo breakdown with aid of LPL (lipoprotein lipase) and HL (hepatic lipase) to release free fatty acids
True
The breakdown products or remnants of lipoprotein particles are taken up by the liver through mediation of ___ and ___, which act as ligands
Apo B and Apo E
Exogenous dietary lipids are processed by the intestine to ___ particles
Endogenouos lipoproteins are synthesized by the ___ in the form of ____ particles
Exogenous - chylomicron particles
Endogenous - liver; VLDL
Cholesterol Synthesis Pathway is also known as ___ Pathway
Mevalonate Pathway
_____ is the rate limiting enzyme for cholesterol synthesis in the Mevalonate Pathway
HMG-CoA Reductase
___ is also known as pyridine-3-carboxylic acid
Niacin
True or False: Niacin belongs to the water soluble B-complex vit family and posses vitamin property only in carboxyl form
False - only in amide form
True or False: Niacin shows anti-hyperlipidemic effects only at lower doses
False - Niacin shows anti-hyperlipidemic effects only at HIGHER doses
How does Niacin affect: LDL-C, HDL-C, and triglycerides?
LDL-C, cholesterol: Decreases
HDL-C: Increases
Niacin acts through the niacin 1/2 receptor, also known as the hydroxycarboxylic acid receptor or GPR ___ A and B
GPR 109 A/B
True or False: Niacin belongs to GPCR family
True
How does niacin (nicotinic acid) prevent TG (adipose) from being converted to free fatty acids in the liver?
(hint: what enzyme is inhibited?)
Inhibits HSL (hormone sensitive lipase) in adipose tissue
-thereby: blocking conversation of TF to FFA in the liver
True or False: As a result of niacin, there is decrease breakdown of TG to free fatty acids
True
What enzyme does Niacin inhibit?
HSL (hormone sensitive lipase)
How does Niacin promote clearance of chylomicrons and VLDL triglycerides?
Enhances LPL activity
How does Niacin affect Apo AI content in plasma?
Niacin increases Apo-A-1 content within the plasma
True or False: In monocytes/macrophages, niacin enhances the cholesterol efflux process by up-regulating efflux transporter (e.g ABCA1)
True
Flushing and dyspepsia are an AE associated with which anti-hyperlipidemic drug?
What worsens flushing?
Niacin
-Caffeine use + Niacin
The most important and serious AE with niacin use is ____, as observed with elevated AST/ALT
hepatotoxicity
Niacin can increase hepatic gluconeogenesis, leading to the _____, an AE.
hyperglycemia
Mechanism for flushing AE in niacin use?
1) The niacin receptor mediates the release of arachidonic acid, produces PGE2/PGD2
2) PGE2 and PGD2 acts on DP1/EP2/EP4 receptors in VSM
3) Vasodilation and redness
Contraindication for niacin use?
Diabetic
What is the major niacin metabolite?
Nicotinuric acid (non-toxic metabolite of nicotinic acid)
What class of anti-hyperlipidemic drugs do fenofibrate and gemfibrozil belong to?
The Fibrates (PPAR alpha agonists)
What receptors to the Fibrates act on?
PPAR’s (Peroxisome Proliferator-Activated Receptors)
Where do Fibrates act?
Liver and Adipose Tissue
When a fibrate binds to PPAR, it promotes heterodimerization of PPAR (nuclear receptor) with ____. This leads the heterodimer complex to bind to the ____, changing gene regulation
RXR (retinoid x receptor)
PPRE (responsive element)
What three genes do PPAR alpha agonists (fibrates) upregulate?
1) LDL receptor
2) Apo CII
3) Apo A1
When two genes do PPAR alpha agonists down regulate?
1) Apo C111 (inhibits LPL)
2) IL-6
Gemfibrozil has major interaction with which drug class?
Statins
- prevents uptake of statins in liver
- interferes with OATP1B1 transporter mediated statin uptake
Statins/gemfibrozil compete for same enzyme, _____, for metabolism
Glucoronosyl transferase
If gemofibrozil is given with statins, both of their plasma levels will increase. Elevated statin level can lead to the AE of ___
myopathy
True or False: Both Gemofibrozil and Fenofibrate have major drug interactions with statins
False - Fenofibrate has NO major drug interactions with statins (no myopathy)
True or False: Fibrates are ok for kids to take
False - NOT ok
Where is PCSK9 (proprotein convertase subtilisin/kexin 9) highly expressed/formed prior to being secreted into bloodstream?
Kidney, liver, intestine
True or False: PCSK9 is localized intracellularly
False - PCSK9 is localized EXTRACELLULARLY
____ are antibodies and inhibit PCSK9 activity
PCSK9 Inhibitors
What are the two PCSK9 inhibitors?
(hint: evolution and ally rows + -cumab)
1) Evolocumab
2) Alirocumab
How do PCSK9 inhibitors increase LDL receptors in membrane?
Inhibiting PCSK9 prevents PCSK9 mediated LDL receptor degradation in lysosomal system
True or False: PCSK9 Inhibitors increase membrane LDL receptors and increase LDL-C clearance from plasma
True
___ is a siRNA targeting PCSK9 mRNA, resulting in degradation of PCSK9 mRNA and limiting PCSK9 protein synthesis
Inclisiran
Which drug inhibits dietary cholesterol uptake?
Ezetimibe
Where does Ezetimibe act?
Intestinal lumen
How does Ezetimibe inhibit luminal cholesterol uptake by jejunal enterocytes?
(hint: what receptor does it block)
Blocks NPC1L1 - cholesterol transport protein
True or False: Ezetimibe reduces 1) cholesterol content for intestinal chylomicron synthesis and 2) delivery of cholesterol load into liver as chylomicron remnants
True
What is a secondary benefit of Ezetimibe?
As cholesterol delivery to liver decreases, liver makes more LDL receptors
___ blocks NPC1L1 present in enterocytes of intestine (mostly jejenum)
Ezetimibe
What drug class does Lomitapide belong to?
MMTP (microsomal triglyceride transfer protein) Inhibitors
Lomitapide binds to ____ in the ER, preventing packaging/assembly of ___ containing lipoprotein bodies, which include both ___ (enterocytes) and VLDL-C____(hepatocytes)
MTTP; ApoB; ApoB48 (enterocytes);
VLDL-C-ApoB100 (hepatocytes)
Major AE with MTTP Inhibitors?
Hepatic toxicity
What are the active ingredients in omega-3 fatt acid?
EPA and DHA (Lovaza, Omytrg)
How does omega-3 act as a anti-inflammatory drug?
Prevents formation of AA
The DHA (omtryg) component in omega 3 supplements are known to increase ___ levels
LDL-C levels
Vascepa contains only one of the active ingredients in omega-3 fatt acids - which one?
Vascepa contains EPA component only
What are the benefit of using vascepta?
Since it only contains EPA (active ingredient in omega 3 fatty acids) - it does NOT increase LDL-C (as DHA component does)
True or False: Vascepa/Icosapent Ethyl prevents plaque formation/inflammatory responses, improves endothelial function, and inhibits platelet aggregation
True
What is a newer agent for treating hyperlipidemia?
1) Bempedoic Acid
2) Evinacumab
How does Bempedoic Acid, a newer agent for treating hyperlipidemia, decrease cellular cholesterol synthesis?
Inhibits ATP Citrate Lyase, the enzyme involved in synthesizing Acetyl-CoA
True or False: Bempedoic Acid is a prodrug that needs to be activated in hepatic tissue
True
Clinical indication for Bempedoic Acid use?
Heterozygous Familial Hypercholesterolemia or persistent, long term atherosclerotic CVD
True or False: Bempedoic Acid is very effective at lowering blood LDL-C levels
True
True or False: Bempedoic Acid can be used as an adjunct to diet and max. tolerated statin therapy
True
There is a DDI with Bempedoic Acid and ___, leading to higher incidences of ___
statins; myopathy
More than _ mg of Simvastatin and _ mg of Pravastatin should be avoided
20 mg ; 40 mg
What anti-hyperlipidemia drug causes a rise in blood uric acid levels?
Bempedoic Acid
____ can be administered in combination with Ezetimibe
Bempedoic Acid
____ is a recombinant IgG4 monoclonal antibody that targets antiopoietin-like protein 3 (ANGPTL3)
Evinacumab
What drug is approved to be an adjunctive therapy for homozygous familial hypercholesterolemia (HoFH)
Evinacumab
Evinacumab bind and blocks_____, an angiopoietan-like protein, thereby sparing LPL/EL activity, improving triglyceride breakdown, and reducing LDL-C levels
ANGPTL3
