Anti-Lipid Drugs Flashcards
Which of these classes of drugs does NOT work by lowering serum LDL?
a. statins
b. bile acid-binding resins
c. NPC1L1 inhibitors
d. PCSK9 inhibitors
e. ACL inhibitors
f. fibril acid derivatives
lower serum LDL:
a. statins (Atorvastatin, Lovastatin)
b. bile acid-binding resins (Colesevelam)
c. NPC1L1 inhibitors (Ezetimibe)
d. PCSK9 inhibitors (Alirocumab)
e. ACL inhibitors (Bempedoic Acid)
lower septum TAG and raise HDL:
f. fibril acid derivatives (Gemfibrozil)
[also vit. B3 (Niacin)]
atorvastatin vs lovastatin
high potency statins: atorvastatin, rosuvastatin, simvastatin
low potency statins: lovastatin, pravastatin, fluvastatin, pitavastatin
recall statins inhibit HMG CoA reductase (lower LDL), also cause modest increase in serum HDL
how to atorvastatin and lovastatin work?
statins = HMG CoA reductase competitive inhibitors
rate-limiting enzyme in hepatic cholesterol biosynthesis —> increased expression of LDL receptor = lower plasma LDL (and IDL)
atorvastatin = high potency statin
lovastatin = low potency statin
Statins are considered first-line LDL-lowering agents; however, patients with this condition will not respond as well. What is?
homozygous familial hypercholesterolemia - due to both alleles of LDL receptor being dysfunctional
what are the 2 adverse reactions associated with statins?
- myopathy (muscle issues) - rarely rhabdomyolysis (elevated creatinine kinase)
- hepatotoxicity - will see modest elevation in liver enzymes
what is the mechanism of action of colesevelam, cholestyramine, and colestipol?
bile acid-binding resins (sequestrant): large cationic polymer that binds anionic build acids in intestinal lumen, preventing reabsorption
—> bile acid elimination drives more bile acid synthesis in liver —> this requires cholesterol synthesis —> unregulated LDL receptors lower plasma LDL/IDL levels
*note resin-induced decrease in hepatic cholesterol is slightly offset by increase in HMG CoA reductase activity - therefore work best in combination with statins
when is colesevelam, cholestyramine, or colestipol use indicated?
bile acid-binding resin (sequestrant): resin-induced decrease in hepatic cholesterol is partially offset by up-regulation of HMG CoA reductase
therefore, work best in combination with statins - most often used in patients requiring additional lowering of atherogenic cholesterol (start with lowest dose, escalate slowly as tolerated/needed)
what adverse reactions are associated with colesevelam, cholestyramine, and colestipol?
bile acid-binding resins
adverse effects are limited to GI tract since resins are not absorbed: dyspepsia, constipation, bloating, flatulence
*not recommended for patients with high TAGs since increased bile acid production is accompanied by modest increase in hepatic TAG synthesis
what is the mechanism of action of Ezetimibe?
Ezetimibe: inhibits NPC1L1 enterocyte cholesterol transporter —> reduced absorption of dietary cholesterol
—> less cholesterol is delivered to liver —> LDL receptor up-regulation —> further lowered serum LDL
works synergistically with statins
bile acid-resins are _____ to statin efficacy, while Ezetimibe is _____ to statin efficacy
bile acid-resins are ADDITIVE to statin efficacy, while Ezetimibe (NPC1L1 inhibitor) is SYNERGISTIC to statin efficacy
When is Ezetimibe use implicated?
Ezetimibe: inhibits NPC1L1 enterocyte cholesterol transporter
works synergistically with statins - main use is in combination with statins (when high potency is not enough) or in patients who can’t tolerate statins
no significant adverse effects
what is the mechanism of action of alirocumab and evolocumab?
PCSK9 inhibitors (mAb) —> increased LDL receptors —> lower serum LDL
recall PCSK9 protease binds hepatocyte LDL receptor and enhances its degradation
when is use of alirocumab or evolocumab implicated?
PCSK9 (enhances LDL receptor degradation) inhibitor (mAb - monoclonal antibodies)
biologics are never first-line because they can’t be given orally and commonly cause injection site reactions
approved for patients with heterozygous familial hypercholesterolemia who don’t respond well to statins alone
what is the mechanism of action of bempedoic acid in lowering serum LDL?
bempedoic acid: competitively inhibits hepatic ATP-citrate lyase (ACL), which is upstream of HMG CoA reductase (rate-limiting step) in cholesterol synthesis
ACL is required for generating acetyl-CoA needed for de novo cholesterol synthesis (the building blocks)
—> up-regulated LDL receptor —> lower serum LDL
when is bempedoic acid use implicated?
bempedoic acid: competitively inhibits hepatic ATP-citrate lyase (ACL), required for generating acetyl-CoA (building blocks of cholesterol synthesis)
LDL lowering activity is additive with statins and ezetimibe (NPC1L1 inhibitor)
approved for oral use in patients with heterozygous familial hypercholesterolemia for which max statin therapy alone is not enough to lower LDL
what are 2 possible significant adverse reactions associated with bempedoic acid?
bempedoic acid: competitively inhibits hepatic ATP-citrate lyase (ACL), required for generating acetyl-CoA (building blocks of cholesterol synthesis)
- hyperuricemia: via inhibition of anion transport in proximal renal tubule (uptakes uric acid from blood) - uric acid is insoluble, can crystallize and cause gout
- tendon rupture
what is the drug class of choice for lowering TAG levels? what is the mechanism of action?
fibrates (fibric acid derivatives): gemfibrozil, fenofibrate
bind/activate nuclear TF PPAR-alpha (peroxisome proliferator-activated receptor) —> LPL (lipoprotein lipase) expression —> increased hydrolysis of VLDL and chylomicron TAGs
also increase HDL by induced hepatic ApoA-I and ApoA-II expression
what is the mechanism of action of gemfibrozil and fenofibrate?
fibrates: bind/activate nuclear TF PPAR-alpha (peroxisome proliferator-activated receptor) —> LPL (lipoprotein lipase) expression —> increased hydrolysis of VLDL and chylomicron TAGs
also increase HDL by induced hepatic ApoA-I and ApoA-II expression
when is use of gemfibrozil or fenofibrate implicated?
fibrates: bind/activate nuclear TF PPAR-alpha —> LPL expression —> increased hydrolysis of VLDL and chylomicron TAGs
also increase HDL by induced hepatic ApoA-I/ApoA-II
use: DOC for hypertriglyceridemia and low HDL - work best for type III lipoproteinemia (high VLDL/IDL, normal LDL) because they don’t really affect LDL levels
what adverse effects are associated with fibrates?
fibrates (gemfibrozil, fenofibrate): bind/activate nuclear TF PPAR-alpha —> LPL expression —> hydrolysis of VLDL and chylomicron TAGs
also increase HDL by induced hepatic ApoA-I/ApoA-II
adverse reactions: GI disturbance (dyspepsia, diarrhea, flatulence)
[you might want to take fibrates with fiber because they will upset your digestion]
what is the mechanism of action of niacin in lowering serum sterol levels?
niacin = nicotinic acid = vit. B3
inhibits FFAs and TAGs release from peripheral adipose/ synthesis in liver —> reduced VLDL, modest reduction in LDL
best drug for increasing HDL (reduces its catabolism)
when is use of niacin implicated in lowering sterol levels?
niacin = nicotinic acid = vit. B3
inhibits VLDL secretion (—>decreased levels) and HDL catabolism (—>increased levels)
indicated for patients with high TAGs/ LDL and low HDL
*use limited by severe cutaneous adverse reactions
what 2 adverse effects are associated with niacin?
niacin = nicotinic acid = vit. B3
inhibits VLDL secretion (—>decreased levels) and HDL catabolism (—>increased levels)
adverse effects:
1. severe cutaneous reactions (flushing, pruritis) - limits use, only available in extended-release to minimize this effect
2. hepatotoxicity
which of these would NOT be effective in lowering serum TAG levels?
a. lovastatin
b. colesevelam
c. ezetimibe
d. alirocumab
e. bempedoic acid
f. gemfibrozil
g. niacin
can lower TAGs:
a. lovastatin: low potency statin
c. ezetimibe: NPC1L1 inhibitor
d. alirocumab: PCSK9 inhibitor
e. bempedoic acid: ACL inhibitor
f. gemfibrozil: fibrate, BEST at lowering TAGs
g. niacin: vit B3
will NOT lower TAGs:
b. colesevelam: bile acid-binding resin - not recommended for patients with significant hypertriglyceridemia because increased bile acid production is accompanied by increase in hepatic TAG synthesis
which of these may actually slightly lower HDL levels?
a. lovastatin
b. colesevelam
c. ezetimibe
d. alirocumab
e. bempedoic acid
f. gemfibrozil
g. niacin
e. bempedoic acid: inhibits ATP-citrate lyase (required for acetyl-CoA synthesis)
as a result, lowers LDL levels but also modestly lowers HDL levels
which of these is associated with myopathy?
a. atorvastatin
b. colesevelam
c. ezetimibe
d. alirocumab
e. bempedoic acid
f. gemfibrozil
g. niacin
statins are associated with myopathy
atorvastatin (high potency) and lovastatin (low potency)
which of these acts synergistically with statins?
a. lovastatin
b. colesevelam
c. ezetimibe
d. alirocumab
e. bempedoic acid
f. gemfibrozil
g. niacin
c. ezetimibe: NPC1L1 cholesterol transporter inhibitor
which of these is rarely associated with adverse reactions?
a. lovastatin
b. colesevelam
c. ezetimibe
d. alirocumab
e. bempedoic acid
f. gemfibrozil
g. niacin
c. ezetimibe: NPC1L1 cholesterol transporter inhibitor
which of these are approved for use in patients with heterozygous familial hypercholesterolemia or ASCVD?
a. lovastatin
b. colesevelam
c. ezetimibe
d. alirocumab
e. bempedoic acid
f. gemfibrozil
g. niacin
d. alirocumab: PCSK9 inhibitor
e. bempedoic acid: ATP-citrate lyase inhibitor
approved for use as adjuncts to maximally tolerated statin therapy
