11/2 Lipid Drugs - Lobel Flashcards
HMG-CoA Reductase inhibitors
aka
mechanism
6 names
STATINS
mechanism: downreg of HMG-CoA reductase (catalyst of rate-limiting step of chol synthesis) and consequential upreg of LDL-receptor (which will clear circulating lipoproteins)
lovastatin
atorvastatin
fluvastatin
pravastatin
simvastatin
rosuvastatin
PCSK9 inhibitors
2
monoclonal antibodies that affect PCSK9, which normally fx in downregulation of LDL-receptors
→ increases concentration of LDLr → improves clearance of atherogenic lipoproteins
alirocumab
evolocumab
cholesterol absorption inhibitor
1
inhibits absorption of dietary chol in the enterocyte
ezetimibe
bile acid sequestrants
aka
3
RESINS
- bile acids are modified cholesterols → normally synthesized in liver, dumped into bile, released into intestines, where they are largely reabsorbed/recirculated
- bile acid sequestrants bind bile in intestines → leads to excretion of bile → compensatory increase in LDLr
colestipol
cholestyramine
colesevelam
niacin
nicotinic acid, vitamin B3
- decreases secretion of VLDL
fibric acid derivatives
2
- effect on tf →→→ increases hydrolysis of TGs, decreases circulation of VLDL
gemfibrozil
fenofibrate
summary table
total body balance of cholesterol
EXOGENOUS
- dietary chol: absorbed in enterocyte, packaged into chylomicrons
- chylomicrons released and give off some TGs
- TGs are hydrolyzed (LPL - lipoprotein lipase)
- CM remnants picked up by liver and utilized to make VLDLs which are then released into systemic circ
ENDOGENOUS
- CM remnants picked up by liver are utilized to make VLDLs → released into systemic circ
- IDL/LDL picked up by liver, converted to bile salts/bile → released into intestines
lipoproteins review
two principle ways a cell can get cholesterol
- uptake of circulating cholesterol (LDL pickup by LDLr)
- de novo cholesterol biosynthesis
cholesterol delivery to cells
- LDL binds to LDLr (found in clathrin-coated pit), is endocytosed, delivered to a low pH compartment
- acidity promotes dissociation of LDL/LDLr
- LDLr circulates back to membrane
- LDL released into lumen of compartment → eventually hydrolyzed by lipases, utilized by cell
de novo cholesterol biosynthesis pathway
acetyl CoA + acetoacetyl CoA → HMG CoA
- HMG CoA synthase
HMG CoA → mevalonate
- HMG CoA reductase
- this is the rate limiting step in de novo chol synthesis!
regulation of cholesterol levels
role of SREBP
cells sense chol levels, use SREBP to adjust LDL uptake and chol synthesis
- sterol regulatory element binding protein is a transcription factor: master regulator of chol levels in cell
in low chol diet…
SREBP active:
- incr chol biosynthesis (via incr HMG CoA reductase synth)
- incr receptor-mediated LDL endocytosis
- overall: plasma LDL decreases!
in high chol diet…
SREBP inactive:
- decr chol biosynthesis (via decr HMG CoA reductase synth)
- decr LDL recpetors
- overall: plasma LDL stays high!
which steps do which drugs affect?
5 drug groups
- statins
* inhibit HMG CoA reductase → decr chol synth → incr LDLr → incr LDL pickup - PCSK9 inhibitors (mAbs)
* incr number of LDLr per cell - resins (bile acid sequestrants)
* prevent reabs of bile acids → bile acids excreted → body chol stores drawn down to make more - ezetimibe
* inhibits uptake of dietary chol and plant sterold - niacin
* decr release of VLDL
(also: fibrins)
statins
mechanism of action
specific effects (TG, LDL, HDL)
competitive inhibitors of HMG CoA reductase
- prevents rate limiting step of chol biosynthesis: HMG CoA → mevalonate
- most effective and best-tolerated agents for dyslipidemia
overall effect: drop in de novo synthesis of chol → incr in chol uptake via LDLr
- inhibit cholesterol synth
- incr expression of LDLr → incr removal of LDL (VLDL, IDL) from circ
- decr hepatic VLDL production
- TG levels > 250 reduced by statins*
- LDL chol levels: some studies show slight incr*
- HDL chol levels: lower by 20-55% (dose-dependent)*
statins
PK
*lovastatin and simvastatin: lactone prodrugs → hydrolyzed to active form
absorption
- absvaries from 40-75% (exception: fluvastatin almost COMPLETE)
- enhanced by food
- half-life: most 1-3hr (atorvastatin 14, rosuvastatin 19)
- take in evening (bc hep cholesterol biosynth is maxed from 12-2am) unless long half-life med
excretion
- high first-pass metabolism by liver → most of dose excreted in bile
- 5-30% excreted in urine
statins
therapeutic use
which are best for severe hyperchol?
- used alone or in combo with resins, niacin, ezetimibe
- TERATOGENIC: contraindicated in pregnant/lactating/likely to become preg women
- some approved for use in children homozygous or heterozygous for fam hypercholesterolemia
atorvastatin & rosuvastatin are the most efficacious agents for severe hypercholesterolemia!
- more TG lowering activity compared to others
statins
adverse effects
1. LIVER ISSUES
- elevation in serum Ala aminotransferase activity (up to 3x normal)
- elevation in ALT (higher than 3x normal)
2012: FDA says routine measurmement during tx no longer recommended. measure initially and then if clinically indicated
2. MYOPATHY
statin tx can reduce occlusive vas events by 40-50% BUT many pt discontinue due to myopathies and other issues (often incorrectly attributed to statins)
- myopathy w/ or w/out elevation in creatine kinase
- intense myalgia (arms/thighs → entire body) & fatigue
- reversible with discont of drug
- rhabdomyolysis → myoglobinuria → renal levels (if CK over 10x normal)
- incidence <0.1% w/out other drugs that incr risk
why do myopathies occur?
- drug interactions (subs metabolized by CYP3A4; inhibitors of organic anion transporter)
-
genetic influences (polymorphisms in liver OAT)
- OAT polypeptide 1B1 (encoded by SLCO1B1) reduces hepatic uptake of active simvastatin acid → accumulation of simvastatin acid in plasma, incr risk of myopathy
red yeast rice
what is it/how does it work
major issues
used my many as an alt tx for hyperlipidemia (bc its a source of statins)
contains 14 active compounds (monacolins) that inhibit hepatic chol synthesis
- monacolin K = lovastatin
major issues:
- there is a lot of variability in monacolin content in RYR products on market → not standardized, often unpublished
- 1/3 of formulations contain citrinin (mycotoxin with various adverse effects incl nephrotox and hepatotox)
PCSK9 inhibitors
mech of action
admin
halflife
monoclonal antibodies (mAbs) against PCSK9 protein (proprotein convertase subtisilin/kexin type 9)
- produced in ER → autocatalysis → secreted
- fx: diverts LDLr from recycling pathway to lysosome for degradation
i.e. PCSK9 inhibitors prevent this from happening!!!
admin/halflife
- subcutaneous admin
- half-life
- avolocumab: 11-17d
- alirocumab: 12d
ezetimibe
mechanism
effects
efficacy
circulation?
selectively inhibits NPC1L1 cholesterol transporter on enterocytes; inhibits absorption of dietary chol
- prevents uptake of dietary cholesterol and plant sterols
- effects:
- decr intestinal delivery of cholesterol to liver
- incr expression of hepatic LDL receptors
- decr cholesterol content of atherogenic particles
by itself, 18% drop in LDL-C
in synergy with statins, addtl 25% decr
circulation?
ezetimibe and active glucuronide metabolite circulate enterohepatically
- delivers agent back to site of action
- limits systemic exposure!
bile acid sequestrants
aka
resins
mech of action and effects
how do you increase the effectiveness of resin?
adverse effects/CAUTION
bind bile acids to prevent reabsorption in the enterohepatic recirculatory pathway
- highly positively charged, so bind negatively charged bile acids
- bound bile acids excreted in stool
- decr in hepatic chol content → incr in LDLr content → incr plasma LDL clearance → lower LDL-C (max in 1-2 weeks)
also results in upreg of HMG CoA reductase → incr in chol synthesis, which partially offsets drop in LDL-C
incr in HDL-C levels of 4-5%
effectiveness
- coadmin of a statin = substantially increased effectiveness
- take with meals or won’t have any effect
adverse effects
- constipation, bloating, heartburn/diarrhea
- rare: malabs of vitK → hypoprothrombinemia, malabs of folic acid
-
CAUTION: resin-induced incr in bile acid production leads to concurrent incr in hepatic TG synthesis
- use with caution in pt with severe hypertriglyceridemea
niacin
nicotinic acid; vitB3
- water soluble
- niacin is converted to niacinamide (nicotinamide) and incorporated into NAD
- excreted in urine in unmodified form, as metabolites
- nicotinamide does not have lipid profiles, but…
niacin has favorable effects on all lipid profiles
- best agent for incr HDL
- lowers TG
- reduces LDL-C
- reduces Lp(a)
adverse effects
- niacin flush (harmless cutaneous vasodil, warmth, pruritus, rashes, dry skin)
- nausea, vomiting
- maybe hyperuricemia, gout
- loss of glycemic control in pt with diabetes; incr onset of diabetes
fibrates
use
mechanism
adverse effects
contraindications
fibric acid derivatives, used to hit hypertriglyceridemia!
activate PPARalpha (peroxisome proliferator-activated receptor alpha) : transcription factor regulating genes that control lipid metabolism
- expressed mainly in liver and brown adipose tissue (less in kidney, heart, sk muscle)
mechanism of action: PPARalpha…
- reduces TG by stimulating fatty acid oxidation
- incr LPL synthesis (enhances clearance of TG-rich lipoproteins)
- reduces expression of apoC-III (inhibitor of lipolytic processing and receptor-mediated clearance → enhanced clearance of VLDL)
- stimulation of ApoAI and apoAII expression → incr HDL levels
main effect: reduce plasma TG
- only see modest decr in LDL in most patients
- incr LDL in some patients as TG levels reduced!
adverse effects:
- may potentiate action of oral anticoags
- incr myopathy risk in patients on statins
- incr chol content of bile → modest incr risk of gallstones
contraindications: patients with renal failure/hepatic dysfx; children; pregnant women
