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M2 Cardio > 11/2 Lipid Drugs - Lobel > Flashcards

11/2 Lipid Drugs - Lobel Flashcards

1
Q

HMG-CoA Reductase inhibitors

aka

mechanism

6 names

A

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

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2
Q

PCSK9 inhibitors

2

A

monoclonal antibodies that affect PCSK9, which normally fx in downregulation of LDL-receptors

→ increases concentration of LDLr → improves clearance of atherogenic lipoproteins

alirocumab

evolocumab

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3
Q

cholesterol absorption inhibitor

1

A

inhibits absorption of dietary chol in the enterocyte

ezetimibe

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4
Q

bile acid sequestrants

aka

3

A

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

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5
Q

niacin

A

nicotinic acid, vitamin B3

  • decreases secretion of VLDL
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6
Q

fibric acid derivatives

2

A
  • effect on tf →→→ increases hydrolysis of TGs, decreases circulation of VLDL

gemfibrozil

fenofibrate

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7
Q

summary table

A
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8
Q

total body balance of cholesterol

A

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
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9
Q

lipoproteins review

A
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10
Q

two principle ways a cell can get cholesterol

A
  1. uptake of circulating cholesterol (LDL pickup by LDLr)
  2. de novo cholesterol biosynthesis
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11
Q

cholesterol delivery to cells

A
  • 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
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12
Q

de novo cholesterol biosynthesis pathway

A

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!
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13
Q

regulation of cholesterol levels

role of SREBP

A

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:

  1. incr chol biosynthesis (via incr HMG CoA reductase synth)
  2. incr receptor-mediated LDL endocytosis
  • overall: plasma LDL decreases!

in high chol diet…

SREBP inactive:

  1. decr chol biosynthesis (via decr HMG CoA reductase synth)
  2. decr LDL recpetors
  • overall: plasma LDL stays high!
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14
Q

which steps do which drugs affect?

5 drug groups

A
  1. statins
    * inhibit HMG CoA reductase → decr chol synth → incr LDLr → incr LDL pickup
  2. PCSK9 inhibitors (mAbs)
    * incr number of LDLr per cell
  3. resins (bile acid sequestrants)
    * prevent reabs of bile acids → bile acids excreted → body chol stores drawn down to make more
  4. ezetimibe
    * inhibits uptake of dietary chol and plant sterold
  5. niacin
    * decr release of VLDL
    (also: fibrins)
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15
Q

statins

mechanism of action

specific effects (TG, LDL, HDL)

A

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)*
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16
Q

statins

PK

A

*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
17
Q

statins

therapeutic use

which are best for severe hyperchol?

A
  • 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
18
Q

statins

adverse effects

A

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
19
Q

red yeast rice

what is it/how does it work

major issues

A

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:

  1. there is a lot of variability in monacolin content in RYR products on market → not standardized, often unpublished
  2. 1/3 of formulations contain citrinin (mycotoxin with various adverse effects incl nephrotox and hepatotox)
20
Q

PCSK9 inhibitors

mech of action

admin

halflife

A

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
21
Q

ezetimibe

mechanism

effects

efficacy

circulation?

A

selectively inhibits NPC1L1 cholesterol transporter on enterocytes; inhibits absorption of dietary chol

  • prevents uptake of dietary cholesterol and plant sterols
  • effects:
  1. decr intestinal delivery of cholesterol to liver
  2. incr expression of hepatic LDL receptors
  3. 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!
22
Q

bile acid sequestrants

aka

resins

mech of action and effects

how do you increase the effectiveness of resin?

adverse effects/CAUTION

A

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
23
Q

niacin

A

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
24
Q

fibrates

use

mechanism

adverse effects

contraindications

A

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

M2 Cardio (22 decks)

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