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820 > Hyperlipidemia Drugs > Flashcards

Hyperlipidemia Drugs Flashcards

1
Q

Antihyperlipidemics - Extrahepatic Drugs

A
  • Lipid absorption inhibitors
  • Bile acid binders
  • Niacin
  • Fibrates
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2
Q

Cholesterol/Fat Absorption Inhibitors (2)

A
  1. Ezetimibe (Zetia)

2. Orlistat (Xenical)

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3
Q

Bile Acid Binding Resins (3)

A
  1. Colesevelam (Welchol)
  2. Colestipol (Colestid)
  3. Cholestyramine (Quetran)
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4
Q

Niacin (3)

A
  1. Niacor - IR
  2. Niacin - SR
  3. Niaspan - ER
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5
Q

Fibrates (2)

A
  1. Gemfibrozil (Lopid)

2. Fenofibrate (Tricor)

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6
Q

HMG-CoA Reductase Inhibitors (7)

A
  • STATINS
    1. Atorvastatin (Lipitor)
    2. Lovastatin (Mevocor)
    3. Pravastatin (Pravachol)
    4. Simvastatin (Zocor)
    5. Fluvastatin (Lescol)
    6. Rosuvastatin (Crestor)
    7. Pitavastatin (Livalo)
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7
Q

MTTP Inhibitors

A

Lopitamide (Juxtapid)

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8
Q

PCSK-9 Inhibition (2)

A
  1. Alirocumab (Praluent)

2. Evolocumab (Repatha)

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9
Q

Antihyperlipidemics - Hepatic Action Drugs

A
  • Statins
  • MTTP Inhibitors
  • PCSK9 Inhibitors
  • Mipomersen
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10
Q

Ezetimibe (MOA)

A
  • Zetia
  • Cholesterol Absorption Inhibitor
  • MOA: selective inhibition of cholesterol absorption at the brush border of the small intestine
  • Blocks Niemann-Pick C1 Like 1 (NPCL1) receptor (transporter of cholesterol to found mixed micelles)
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11
Q

Ezetimibe Therapeutic/Adverse Effects

A
  • Decreases LDLs
  • No effect on absorption of fat-soluble vitamins, TGs, or bile acids
  • Can use alone with dieting or in combination with statins
  • Main adverse effect = flatulence. May also produce diarrhea and myalgia
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12
Q

Orlistat (MOA)

A
  • Xenical (Rx) or Alli (OTC)
  • Fat absorption inhibitor
  • MOA - inhibitor of pancreatic lipase, decreases the absorption of dietary fat by about 25%
  • Pancreatic lipase is released into the duodenum to break down larger dietary fat globules into FFAs
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13
Q

Orlistat Therapeutic Effects

A
  • Primarily used to treat obesity

- Studies indicate that it also has additional effect to decrease LDL levels obese individuals

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14
Q

Zetia ADME

A

A: Zetia is absorbed, glucuronidated and reexcreted into the gut (Plasma peak concentration is 4-12h post dosing)
D: Zetia is systemically distributed to a limited degree, ~90% is protein bound
M: Zetia is glucuronidated.
E: >80% are eliminated in feces, Zetia systemic half life = 22h

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15
Q

Orlistat ADME

A

A: Orlistat is poorly absorbed systemically.
D: Orlistat stays in gut
M: Minimal metabolism in gut epithelium and microflora
E: >80% eliminated in feces

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16
Q

Bile Acid Binding Resins MOA

A
  • Bind negatively charged bile acids in the small intestine that are made from cholesterol
  • Resin/bile acid complex is excreted in the feces
  • Hepatocytes must increase conversion of cholesterol to bile acids to compensate for loss
  • Upregulates LDL receptors in liver to increase hepatic intake of cholesterol to convert to bile to replace what is lost, decreases plasma LDL
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17
Q

Bile Acid Binders Therapeutic Effects

A

Therapeutic Uses

  • Moderate decrease in LDL levels, increases HDL
  • Large molecules, insoluble in water, not absorbed or metabolized, totally excreted in feces
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18
Q

Bile Acid Binders Adverse Effects

A
  • GI effects: most common (constipation, nausea, flatulence), fiber supplements may help
  • Impaired absorption at high doses of fat-soluble vitamins
  • Decreases absorption of tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, and thiazide diuretics (take 1-2 hours before or 4-6 hours after)
  • *Colesevelam is better tolerated and does not decrease the absorption of other drugs**
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19
Q

Bile Acid Binder Cautions/CIs

A
  • Good safety record for long periods
  • Pregnancy - preferred drug therapy during pregnancy (monitor fat soluble vitamins)
  • Cholelithiasis (biliary stores) or complete biliary obstruction, so CI if bile acid secretion is impaired
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20
Q

Bile Acid Binder ADME

A

A: Not systemically absorbed
D: Stays in the gut
M: Not metabolized
E: 99.95% excreted in feces

21
Q

Niacin (MOA)

A
  • Nicotinic Acid
  • Broad lipid-lowering ability but clinical use is limited due to unpleasant side effects

MOA
-Niacin strongly inhibits lipolysis in adipose tissue to lower circulating FFAs which is used for TG synthesis and then VLDL/LDL ultimately

22
Q

Niacin Therapeutic Effects

A
  • Lowers plasmalevels of cholesterol (LDL by 5-25% and TG (20-50%)
  • Most effective antihyperlipidemic agent for raising plasma HDL levels (15-35%)
23
Q

Preparation of Niacin

A
  • Immediate-release - Niacor - truncal and facial flushing (52-100%)
  • Sustained-release - (Slo-Niacin) absorbed over 12-24 hours, dietary supplement NOT APPROVED for dyslipidemia, some linked to hepatotoxicity and liver failure
  • Extended-release - Niaspan (absorbed ober 8 hr), FDA-approved, lower incidence of flushing and reduced risk of hepatotoxicity
24
Q

Niacin ADME

A

A: Peak plasma concentrations: Niacor = ~30-60minutes; Niaspan = ~5h, highly variable
D: Broad systemic distribution
M: Rapid 1st pass metabolism - handled by numerous enzymes to become nicotinamide adenine dinucleoide, nicotinuric acid, etc.
E: 60-76% in urine, only 12% as a parent compound

25
Q

Prevention of Cutaneous Flush

A

Take aspirin or ibuprofen 30 minutes prior to taking niacin to decrease flush.

26
Q

Niacin Adverse Effects

A
  • Cutaneous flush = main symptom
  • Nausea, vomiting, abdominal pain, flushing and tachycardia
  • Inhibits tubular secretion of uric acid
  • May impair glucose tolerance (caution with diabetes)
  • Hepatotoxicity
27
Q

Fibrates (MOA)

A
  • Gemfibrozil or Fenofibrate
  • MOA: increases LPL activity by activating PPARs which is a transcription factor for LPL. LPLs then decrease TG levels by hydrolyzing triglycerols in CMs and VLDLs. Also increase HDL
28
Q

Fibrates Therapeutic Uses

A
  • Decrease triglyceride levels (25-50%)

- Increase HDL cholesterol levels (10-30%) - first line to reduce risk of pancreatitis in patients with high plasma TGs

29
Q

Fibrates Adverse Effects

A
  • Mild GI disturbances
  • Predisposition to form gallstones
  • Increased hepatotoxicity from increased transaminases
  • Clofibrate - significant number of malignancy-related deaths
  • Myositis - more common with Gemfibrozil since it inhibits metabolism of statins, fenofibrate doesn’t do this
30
Q

Fibrate DI/CI

A

DI: competes with coumadin thus potentiating anticoagulant activity (monitor prothrombin)
CI: patients with severe hepatic and renal dysfunction or pre-existing gall bladder disease

31
Q

Fibrate ADME

A

A: Peak plasma concentrations: Lopid = ~1-2 hours
D: Broad systemic distribution, plasma bound
M: rapid 1st pass metabolism
E: 60-70% eliminated as glucuronidated compound in urine, less than 2% is parent compound, half life ~20-22h

32
Q

MTTP Inhibition

A
  • Lomitapide (Juxtapid)
  • MTTP is essential fortransferring TG to ApoB48 in enterocytes and ApoB100 in hepatocytes
  • Inhibiting this inhibits the production of chylomicrons and VLDL
  • CYP3A4 metabolizes it
  • GI effects are most common SE
  • Comparable results to Zetia with slightly more adverse events (considered mild and safe)
33
Q

Statins MoA

A
  • Analogs of HMG-CoA, a precursor to cholesterol, inhibits HMG-CoA reductase competitively
  • Depletion of intracellular cholesterol leads to elevated levels of cellular LDL receptors to increase cholesterol uptake from circulation
  • Decreases cholesterol synthesis, increases catabolism of LDLs, and smaller increases of HDL and decreases of TGs
34
Q

Statins Therapeutic Uses

A
  • Decreases total and LDL cholesterol (1st line for LDL reduction)
  • May be useful for those with or without CVD
  • Pleiotropic effects (non-lipid)
35
Q

Statin’s Pleiotropic Effects

A
  • Regression of plaque size
  • Increased endothelial function
  • Stabilizes platelets
  • Decreases plasma fibrinogen
  • Decreases inflammatory markers
36
Q

Statin Toxicity

A
  1. Hepatotoxicity - rare, reversible
    - Increases serum aminotransferase
    - Not severe unless already has a liver disorder (CI)
    - Check liver function before prescribing
  2. Myopathy - rare, dose-related
    - Myalgia, muscle weakness, skeletal muscle pain
    - Encourage patient to report unexplained muscle pain
    - Monitor CPK periodically
    - Increased risk when used with fibrates (gemfibrozil), niacin, inhibitors of CYP3A4/statins metabolized by CYP3A4
37
Q

Cerivastatin

A
  • Removed from market
  • Caused death from rhabdomyolysis
  • Especially when used with gemfibrozil
38
Q

Inhibitors of CYP3A4

A
  • Erythromycin
  • Clarithromycin
  • Ketoconazole
  • Itraconazole
  • Gemfibrozil
  • Many HIV drugs
  • Grapefruit juice
39
Q

Statins + When to Take Them

A
  • *Depends on half life**
  • Atorvastatin, rosuvastatin, pravastatin all have long half lives and can be taken at any time of day
  • Simvastatin, lovastatin, fluvastatin have short half lives and have to be taken in the evening (most cholesterol synthesized while sleeping)
40
Q

Bempedoic Acid

A
  • New drug that inhibits cholesterol synthesis

- Inhibits ACL, protein further up the pipeline than statins

41
Q

PCSK9 Inhibitors

A
  • Antibodies being tested as therapeutics
  • Binds to LDLR and induces endosomal uptake and degradation
  • Decreases LDLR and increases circulating LDL
  • Approved for heterozygous familial hypercholesterolemia and clinical ASCVD who need additional reduction of LDL-C
  • DRAMATICALLY lowers LDL, found to be a very safe drug
42
Q

Drug Combinations

A

-If single drug with diet/exercise/life change doesn’t control lipidemia, THEN combine 2+ drugs
Examples
1. Statin + BAB: increases LDL receptors which decreases LDL by 42%
2. Statin + Fibrates: increases myopathies potential
3. ER Niacin/Lovastatin (Advicor, Simcor): decreases LDL, TG, and increases HDL with less flushing and low myopathy/liver damage compared to each alone
4. Ezetimibe + Simvastatin/Ator/Prav/Lova: significantly decreases LDL below that obtained with a statin alone

43
Q

Preggo + Lipid-Lowering Drugs

A
  • Lipid-lowering drugs tend to be completely or relatively contraindicated during pregnancy because of the essential role of cholesterol in fetal development
  • DON’T use statins. BAB are the safest
  • Stop statins ~6 months before conception ideally
44
Q

HDLs

A
  • Protective lipoproteins that decrease risk of CHD
  • Participates in reverse cholesterol transport (excess from cells is taken up to the liver for excretion)
  • HDL = anti-inflammatory, antioxidative, platelet antiaggregatory, anticoagulant, and profibrinolytic activities
  • Antioxidant enzymes in HDL = paraoxonase, PAF acetylhydrolase, glutathione peroxidase
45
Q

HDL Beneficial Effects

A
  1. Increase reverse cholesterol transport
  2. Increased NO and prostaglandin effects on smooth muscle/platelets
  3. Inhibits platelet and monocyte binding to damaged endothelium cells
46
Q

Illuminate Study

A

-15K+ enrolled with coronary artery disease
-Gave some Torcetrapib (HDL promoter) + Atorvastatin and some Atorvastatin alone
Increased HDL (71.1%), decreased LDL (24.9%), decreased TG (9%)
-HOWEVER, the combination also increased BP significantly and increased mortality of patients

47
Q

Hoffman LaRoche

A
  • Dalcetrapib
  • Increases HDL, but no clinical benefits
  • HDL not a simple molecule, complex subcellular particle. Can become pro-inflammatory in oxidative environments
  • Proteomic, lipidemic studies are ongoing to better understand the link to CVD
  • Overall, cholesterol efflux is the best functional marker between CVD and HDL
48
Q

Drugs that Alter Serum Lipoprotein Levels

A

All of the ones in this chapter excluding MTTP inhibitors and PCSK9 Inhibitors

820 (19 decks)

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