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drug action i > Block 2 - Dyslipidemia Pharm > Flashcards

Block 2 - Dyslipidemia Pharm Flashcards

1
Q

What are some non-pharms of treating HLD?

A
  1. Maintain healthy diet and weight
  2. Better compliance
  3. Avoid tobacco
  4. Exercise (150-160 min/week)
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2
Q

What are pharm options of HLD?

A
  1. HMG CoA reductase inhibitors
  2. Cholesterol synthesis inhibitors
  3. Cholesterol absorption inhibitors
  4. Fibric Acid derivatives
  5. Bile-acid binding resins
  6. Niacin (nicotinic acid)
  7. Newer drug agents – PCSK9 inhibitors, Lomitapide, and others
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3
Q

What are the mechanism addressed using lipid lowering therapy?

A
  1. Improved endothelium-dependent vasodilation
  2. Stabilization of atherosclerotic lesions
  3. Reduction of inflammatory stimuli
  4. Prevention or slow progression of atherosclerotic lesions
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4
Q

What are the hyperclosterolemia drugs?

A
  1. Cholesterol synthesis inhibitors (Statins and Bempedoic Acid)
  2. . Cholesterol absorption inhibitors and sequestrants
  3. Niacin or Fibrates
  4. PCK9 inhibitors
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5
Q

What are the hypertriglyceridemia drugs?

A
  1. Fibrin acids
  2. Niacin
  3. Eicosapentaenoic acid (EPA) & Fish oils
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6
Q

What is the MOA of statins?

A

Competitively inhibits the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (in nM range) – which is the rate limiting step for cholesterol biosynthesis

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7
Q

How do statins work?

A

Decreases cholesterol synthesis producing a compensatory increase in the number of cell surface hepatic LDL receptors → Increase plasma LDL clearance

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8
Q

Describe the mechanisms of Statin activity?

A
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9
Q

What is the purpose of lactone on statins?

A

Active center and binds to HMG binding site

Lovastatin is hydrolyzed to resemble intermediate while Atorvastatin already resembles intermediate

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10
Q

What falls under high intensity statin therapies?

A

Daily dose lowers LDL–C on average approximately ≥50%

  1. Atorvastatin (40-80 mg)
  2. Rosuvastatin (20 mg)
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11
Q

What is considered moderate intensity statins?

A

Daily dose lowers LDL–C on average approximately 30% to <50%

  1. Atorvastatin 10 (20) mg
  2. Rosuvastatin (5) 10 mg
  3. Simvastatin 20–40 mg‡
  4. Pravastatin 40 (80) mg
  5. Lovastatin 40 mg
  6. Fluvastatin 40 mg BID
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12
Q

What is considered low intensity therapy?

A

Daily dose lowers LDL–C on average approximately <30%

  1. Pravastatin 10-20 mg
  2. Lovastatin 20 mg
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13
Q

What study noticed that Satins reduced hsCRP → fall in LDL?

A

CHEST study

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14
Q

What study saw pravastatin reduced CRP by 17%?

A

PRINCE study

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15
Q

What is the therapeutic benefits of HMG CoA reductase inhibitors?

A
  1. Reduce major coronary events
  2. Reduce mortality
  3. Reduce coronary procedures
  4. Reduce stroke
  5. Reduces total mortality
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16
Q

What are some counseling points associated with satins?

A

Pravastatin and pitastatin are metabolized with CYP3A4 (excreted in bile unwanted)

Fluvastatin and Rosuvastatin by CYP2C9

CYP3A4 is a source of DDIs

Not safe for pregnancy or breast feeding

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17
Q

What are the side effects associated with statin?

A
  1. Muscle pain (myalgia),
  2. Myopathy and Rhabdomyolysis (Increases to 2% with niacin and 3% with fibrates)
  3. Hepatotoxicity and liver damage (rare)
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18
Q

What are cormordities for statin ADRs?

A
  1. Impaired hepatic (absolute) or renal (caution) function
  2. CYP3A4 drugs (Fibrates, Niacin)
  3. Unexplained increase in ALT levels
  4. > 75 YO
  5. History of stroke
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19
Q

How common fatal rhabdomyolysis with statin?

A

Class effect
Increased by combo with vibrates (gemfibrozil) or niacin

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20
Q

What is the MOA of bempedoic acid?

A
  1. An oral pro-drug, activated in the liver, that inhibits the ATP-citrate lyase (ACLY)
  2. Deceases cholesterol synthesis by inhibition of the ATP citrate lyase
  3. The decrease in cholesterol upregulates the LDL-R, leading to a increase in LDL-C clearance
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21
Q

What is the importance of ATP citrate lyase?

A

enzyme found upstream of HMG CaA reductase used for cholesterol biosynthesis

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22
Q

Brand of Bempedoic Acid?

A

Nexletol

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23
Q

Common ADRs of Nexletol?

A
  1. Muscle spasm
  2. Pain in back or limbs
  3. Gout
  4. Diarrhea (GI problems)
  5. Tendon rupture
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24
Q

Common Dis of Bempedoic Acid?

A

Drug increases simvastatin and pravastatin blood levels

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25
Q

What is the MOA of Ezetimibe?

A

Zetia is a potent and specific inhibitor of dietary and biliary cholesterol absorption that works in the brush border of the small intestine to inhibit the absorption of cholesterol by inhibiting the intestinal Cholesterol Transporter (Niemann-Pick C1-Like 1 protein (NPC1L1))

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26
Q

How is ezetimibe metabolized?

A

A glucuronide (EZEG) – which has 400x greater potency

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27
Q

Fibrate MOA?

A

Alters gene transcription via activity at the peroxisomal proliferation activated receptor (PPAR-α)

One of the drugs of choice for hypertriglyceridemia

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28
Q

What is a PPAR-a?

A

Nuclear receptor that modulates genes associated with fatty acid regulation

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29
Q

What are the primary effects of vibrates on liver and adipose tissue?

A
  1. Increase LPL expression → decreased chylomicron and VLDL and plasma TG
  2. Increase LDL size (less arthogenic)
  3. Increase Acyl-coA synthase → fatty acid oxidation
  4. Increase apoA-I and apoA-II synthesis → Increase HDL-C and reverse cholesterol transport
  5. Decrease Hepatic apoC-III synthesis → Decrease plasma triglycerides
  6. Increase anti-inflammatory effects on arterial wall
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30
Q

What are the lab actions of fibrin acids?

A
  1. Lowers TGs 30–60%
  2. Lowers total cholesterol ~20-40%
  3. Lowers LDL-C ~5–20% (with normal TGs)
  4. May raise LDL-C (with high TGs)
  5. Raises HDL-C ~5–20%
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31
Q

ADRs of fibrates?

A
  1. Increase risk of gall stones (cholecystitis)
  2. Fibrates+Statin increase myopathy
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32
Q

What is nicotine acid? Is it first line?

A

Niacin or Niacor is a Water soluble B-complex vitamin

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33
Q

Niacin MOA?

A
  1. Inhibits lipolysis of triglycerides, reducing FFA mobilization from the periphery
  2. inhibits hormone-sensitive lipase in adipose tissue, reducing the breakdown of triglycerides to free fatty acids and the transport of free fatty acids to the liver
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34
Q

What happens in the liver when Niacin is administered?

A
  1. Decreased TG synthesis → Decreased hepatic VLDL production
  2. Niacin inhibits hepatocyte diacylglycerol acyltransferase-2 (DGAT-2), a key enzyme for triglyceride synthesis
  3. Increased Hepatic and plasma VLDL → lowers LDL (which eventually comes from VLDL)
  4. Decreases HDL-apoAI clearance leading to increase HDL-C levels
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35
Q

If Niacin increase HDL and decreases Lpa with is niacin not used that often for HLD?

A
  1. Side effects, especially in combination with other lipid reducing medication’s
  2. Difficult to dose
36
Q

Common ADRs of Niacin?

A
  1. Flushing
  2. Skin rashes
  3. Dyspepsia
  4. Hepatotoxicity
  5. Muscle Pain
  6. Avoid in patients with gout and peptic ulcers
  7. May worsen diabetes or glucose intolerance @ higher doses
  8. Avoid in pregnancy
37
Q

What must you watch out for when someone is taking both Niacin and statins?

A

Myopathy may occur → reduce statin dose to 25% max

38
Q

What study placed the role of niacin in lipid therapy into question that removed niacin/statin combos?

A

HPS2-THRIVE study

39
Q

What is Slo-Niacin?

A

“Polygel” Controlled-release niacin formulation which may help reduce ADRs, especially flushing

40
Q

What is Niaspan?

A
  1. QD treatment of cholesterol and lipid disorders
  2. HydroGel Programmed-Release formulation
  3. Pricey, but minimizes flushing
41
Q

What is bile acids?

A

Amphipathic polar derivatives of cholesterol necessary for absorption of sterols, fats, and fat soluble vitamins

42
Q

How is bile acid eliminated?

A

Secreted into the intestine (~97%) returns, via the enterohepatic circulation, to the liver.

43
Q

What are the benefits of anion-exchange resins?

A

“Selectively” bind the negatively charged bile acids

44
Q

What are the bile acid sequestrant resins? Counseling point?

A

cholestyramine and colestipol

Take other medications at least an hour prior to use so that it may not impair absorption of other drugs

45
Q

How does colesevelam differ from the other bile acid sequestrate?

A

Water insoluble polymer that is not hydrolyzed by digestive enzymes, and not absorbed from the GI tract into the systemic circulation

Better GI tolerability and may have less potential for drug interactions

46
Q

What is the MOA of bile acid sequestrates?

A

Bind bile acids in the intestine, forming insoluble complexes which are eliminated in the feces leading to compensatory mechanisms

47
Q

What are the compensatory mechanisms of bile acid sequestrants?

A
  1. Reduction in the re-uptake of bile acids increases 7-hydroxylase activity (the enzyme responsible for synthesis of bile), due to the loss of feedback inhibition
  2. Increases in 7-hydroxylase activity leads to increased conversion of cholesterol into bile acids
  3. Increased utilization of cholesterol to increase bile acid synthesis, increases LDL receptors, which increases hepatic uptake of plasma LDL.
48
Q

What mechanism limits BA sequestrates use in certain pateints?

A

increase cholesterol synthesis which may increase VLDL

49
Q

DDIs or BA sequestrates?

A

Binds polar drugs such as warfarin, digoxin, thyroxine and statins… take other medications at least 1 hr before taking the resin
ADEK

50
Q

ADRs and absorption of BA sequestrants?

A
  1. Constipation, nausea, gas
  2. No absorbed systemically
51
Q

Why shouldn’t BA sequestrants be used as a monotherpay?

A

Should not be used as monotherapy in patients with hypertriglyceridemia since they will likely increase triglyceride synthesis

52
Q

Brand of cholestryamine?

A

Questran

53
Q

Brand of Colestipol?

A

Colestid

54
Q

Brand of Colesevelam?

A

WelChol

55
Q

What is the MOA of Omega-3 Fatty acid?

A
56
Q

Lovaza indication? Dosage form? Effects?

A

Severe hyperTG
900 mg of highly purified ethyl esters of omega-3 fatty acids from fish oils.
Reduce TG, TC, increases HDL 9% and LAL-C by 44.5%

57
Q

What are the Omega-3-acid ethyl esters ADR?

A
  1. include burping, mild flu-like symptoms, upset stomach, change in sense of taste
  2. Avoid if fish or shell fish allergy
58
Q

What is the appropriate dosing for OTC fish oil for it to have effect?

A

Up to 14 capsules/day for appropriate dosing

59
Q

What is Vascepa?

A

Synthetic ethyl eicosapentaenoic acid (EPA) without DHA

60
Q

What is EPA?

A

Reduces hepatic VLDL synthesis and secretion, and enhances TG clearance from circulating VLDL particles

61
Q

Why is DHA not commonly used?

A

DHA was associated with a greater reduction in TG, but a greater increase in LDL-C compared to EPA

62
Q

Vascepa indication? ADRs?

A

Hypertriglyceridema

indicated as an adjunct to maximally tolerated statin therapy

EPA-only Vascepa may not elevate LDL-C

63
Q

What is familial hypercholesterolemia?

A

An inherited genetic disorder resulting in high levels of LDL-C and increased risk of atherosclerosis

64
Q

What are the risks of heterozygous FH?

A

risk of premature cardiovascular disease and death affecting 1:2500 people

65
Q

What is the the difference between heterozygous and homozygous FH?

A

Heterozygous FH is characterized by high LDL cholesterol and a family history of high cholesterol, atherosclerosis, early heart disease or stroke

Homozygous FH is rare (~1 in a million) and characterized by extremely high levels of LDL cholesterol and symptoms seen in childhood

66
Q

What is used to treat FH?

A

Lomitapide(Juxtapid)

67
Q

What is the MOA of Lomitapide?

A

Inhibits themicrosomal triglyceride transfer protein(MTP or MTTP) which is necessary forvery low-density lipoprotein(VLDL) assembly and secretion in the liver.

68
Q

What is MTP?

A

(microsomal triglyceride transfer protein) is responsible for lipidation (or transfer of triglycerides) onto apoB48 containing chylomicrons in the gut and onto apoB100 containing VLDL particles in the liver.

69
Q

What does the inhibitor of MTP look like?

A

Blocking MTP reduces hepatic VLDL, LDL and Lp(a) production and intestinal chylomicron formation

70
Q

What are the metabolic effects of lomitapide?

A

Decreases LDL-C, TC, apo B, TG, and non HDL

71
Q

What are the main considerations of Lomitapide?

A

Hepatoxicity risk → only available through REMS program

72
Q

What is the role of PCSK9?

A

a protein secreted by hepatocytes which “chaperones” the LDL receptor (LDL-R)

inhibits LDL receptor recycling and earmarks LDL-Rs for lysosomal degradation

73
Q

What is the role of LDL receptors?

A

Responsible for the removal of LDL particles from blood and into hepatocytes

74
Q

What are MOA of PCSK9 inhibitors?

A

Monoclonal antibodies that bind to PCSK9 protein, thereby inhibiting its binding to and effects on the LDL receptor → reducing LDL levels and degradation of LDL recepotrs

75
Q

What are the PCSK9 meds?

A

Repatha (evolocumab) and Praluent (alirocumab)

76
Q

ADRs of Repatha (evolocumab) and Praluent (alirocumab)?

A
  1. Sore throat
  2. ISR
  3. Flu-like symptoms
  4. Elevated LFT
  5. Elevated plasma glucose and HbA1C
77
Q

What happens if you have a rare serious reaction to Repatha (evolocumab) and Praluent (alirocumab)?

A

Discontinue medication if showing signs of anaphylasis

78
Q

Why is Miomersen not used today?

A

Kynamro’s hepatoxcity risk was too high

79
Q

What was the MOA of Miomersen?

A

antisense oligonucleotide which binds to messenger RNA coding for apolipoprotein B-100 (apoB-100), the main component of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL

80
Q

What is Inclisiran?

A

small interfering RNA (siRNA) which inhibits hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia

familial heterozygous hypercholesterolemia

81
Q

Dosing of Inclisiran? ADRs?

A

SQ injection Q3M then 6 month

  1. Pain
  2. Diarrhea
  3. Cough, SOB
82
Q

What is Angiopoietin-like protein 3 (ANGPTL3)?

A

An inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), retarding clearance of triglyceride-rich lipoproteins upstream of low-density lipoprotein production, thereby increasing plasma triglycerides, LDL cholesterol, and HDL cholesterol.

83
Q

MOA of Evinacumab (Evkeeza)

A

binds to and inhibits the ANGPTL3, which promotes VLDL clearance and decreases hepatic VLDL secretion, thereby reducing the conversion of VLDL to LDL, resulting in decreased LDL-C levels.

84
Q

Loss-of-function mutations in ANGPTL3 results in ___ and _____

A

Hypolipidemia and reduction in CV risk

85
Q

Indication for Evinacumab?

A

homozygous familial hypercholesterolemia (HoFH).

86
Q

ADR of Evinacumab?

A
  1. nasopharyngitis (runny nose, rhinorrhea, nasal congestion)
  2. influenza-like illness
  3. sore throat
  4. dizziness
  5. nausea

drug action i (32 decks)

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