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CPR Exam 1 > Drugs For Lipid Disorders > Flashcards

Drugs For Lipid Disorders Flashcards

1
Q

All Statins only have 40-75% absorption except for which one?

A

Fluvastatin is nearly completely absorbed

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2
Q

What effect does food have on Statin Absorption?

A

Food Increases Statin absorption

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3
Q

All Statins have half-lives of 1-3hrs except for which 3?

A

Atorvastatin (14hrs)
Pitavastatin (12hrs)
Rosuvastatin (19hrs)

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4
Q

How is the bulk of the absorbed dose of statins excreted?

A

Via bile

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5
Q

What enzyme do Statins function to inhibit?

A

Statins function to inhibit HMG-CoA Reductase, the rate-limiting enzyme in cholesterol synthesis

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6
Q

By how much can Statins cause a reduction in circulating LDL levels.

A

Statins can cause a reduction in circulating LDL levels by 20-55%

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7
Q

Order the Statins from Highest Potency to Least

A 
(Highest)
Atorvastatin=Rosuvastatin
Simvastatin
Pitavastatin=Lovastatin=Pravastatin
Fluvastatin 
(Lowest)
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8
Q

What Statins are metabolized primarily by CYP 3A4

A

Atorvastatin, Simvastatin, Lovastatin

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9
Q

Which statins are metabolized primarily by CYP 2C9

A

Fluvastatin and Rosuvastatin

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10
Q

Which statin is not metabolized by CYP’s?

A

Pravastatin is not metabolized by CYP’s

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11
Q

Which statin undergoes only limited Biotransformation via CYP 450?

A

Pitavastatin

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12
Q

What are some of the adverse effects of statins?

A

Liver: elevation of Serum Aminotransferase activity (up to 3x normal in Pt’s w/ liver dz/alcohol abuse)

Muscle: Creatine Kinase Activity may increase (particularly in Pt’s have a high level of physical activity). Rhabdomyolysis -> Myoglobinuria (rare but can lead to renal injury). Myopathy (increased risk if Pt also taking fibrates).

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13
Q

What Drug interactions are important to consider with Statins?

A

Statins increase Warfarin levels

Use caution with other agents that inhibit, compete with, or induce CYP450 enzymes

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14
Q

What Contraindications should one consider with Statins?

A

Contraindicated in:

  • Pregnant women, lactating women, or women who may become pregnant.
  • Pt’s w/ Liver Disease
  • Pt’s with Skeletal Muscle Myopathy
  • Child than don’t have at least heterozygous Familial Hyperlipidemnia
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15
Q

How well is Niacin (Nicotinic Acid, Vit B3) absorbed? What is its first pass metabolism like? How about its half-life? What do its absorption and half-life mean in regards to dosing it?

A

Niacin (Nicotinic Acid, Vit B3) is well absorbed, but it has extensive first-pass metabolism, and it only has a half-life of approximately 60 minutes. Thus, Niacin must be given 2-3 times a day.

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16
Q

What compound is Niacin (Nicotinic Acid, Vit B3) converted into once in the body? Subsequent to its Biotransformation, what is it then incorporated into?

A

Niacin (Nicotinic Acid, Vit B3) is converted into Nicotinamide once in the body, it is then incorporated into Nicotinamide Adenine Dinucleotide (NAD)

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17
Q

What is the mechanism of action of Niacin (Nicotinic Acid, Vit B3)?

A

Niacin (Nicotinic Acid, Vit B3) functions to inhibit lypolysis of TAG’s in adipose tissue (the primary producer of FFA’s) by acting on Hormone Sensitive Lipase

This decreases FFA’s, causing the liver to produce less VLDL, and LDL levels decrease. HDL catabolism is decreased. Fibrinogen Levels are reduced. TPA levels are increased.

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18
Q

WHat are some of the potential adverse effects of Niacin?

A
  • Most common side effect is an intense cutaneous flush accompanied by an uncomfortable warmth when the drug is started or when its dose is increased.
  • Pruritis
  • Rashes
  • Dry Skin and Mucous Membranes
  • Acanthosis Nigricans
  • Can Increase Uric Acid levels
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19
Q

What may you do the help relieve the Intense cutaneous flushing and uncomfortable warmth that can accompany starting a Niacin (Nicotinic Acid, Vit B3) prescription, or increasing its dose?

A

Aspirin taken before Niacin, or a once daily Ibuprofen may be taken to reduce the effects of this side effect as it is PG-mediated

20
Q

What are some of the contraindications for Niacin (Nicotinic Acid, Vit B3)?

A
  • Hepatotoxicity can occur in pt’s with Liver issues (Liver function -aminotransferases - should be monitored at baseline)
  • Avoid in Pt’s w/ Hepatic Disease/Active Peptic Ulcer
  • Use caution in diabetics as it could lead to Niacin-Induced Insulin resistance and subsequent diabetes (hyperglycemia can lead to Acanthosis Nigricans)
21
Q

What are the two Fibric Acid Derivatives (Fibrates) we discussed?

A

Fenofibrate

Gemfibrozil

22
Q

How do meals effect the absorption of Fenofibrate and Gemofibrozil?

A

Fenofibrate and Gemfibrozil are well absorbed (90%) when taken with a meal, but less so when taken on an empty stomach

23
Q

Does Fenofibrate or Gemfibrozil have a longer half-life?

A

Gemfibrozil only has a half-life of 1.5hrs whereas Fenofibrate’s half-life is 20hrs

24
Q

What enzyme do Fenofibrate and Gemfibrozil function as Agonists for?

A

Fenofibrate and Gemfibrozil function as Agonists for Peroxisome Proliferator-Activated Rceptor alpha (PPARa)

25
Q

What function of Peroxisome Proliferator-Activated Receptor alpha (PPARa) is stimulated by Fenofibrate and Gemfibrozil?

A

Fenofibrate and Gemfibrozil function to activate PPARa to bind to DNA to alter expression:

  • lipoprotein lipase, apo A-I, and apo A-II expression is increased
  • apo C-III expression is decrease
26
Q

What effects are caused by the Alteration in gene expression resulting from the activation of PPARa by Fenofibrate and Gemfibrozil?

A
  • Increased oxidation of fatty acids in the liver and striated muscle
  • Increased lipolysis of TG via lipoprotein lipase
  • Decreased intracellular lipolysis in adipose tissue
  • VLDL levels decrease
  • LDL levels modestly decrease in most Pt’s (though they can increase as TG levels are reduced)
  • HDL levels are increased
27
Q

In what situations are Fibric Acid Derivatives (Fibrates), Fenofibrate and Gemfibrozil, most useful?

A

Fenofibrate and Gemofibrozil are most useful when dealing with:

  • Hypertriglyceridemias where VLDL predominates
  • Dysbetalipoproteinemia
  • Hypertriglyceridemia resulting from treatment with viral protease inhibitors
28
Q

What are some of the possible adverse effects of Fibrates (Fenofibrate and Gemfibrozil)?

A
  • Mild GI disturbances most common, usually subside on their own
  • increased risk of cholelithiasis
  • Liver: increased serum transaminases (up to 3x normal)
  • Myositis (evaluate for muscle weakness/tenderness)
29
Q

What are some of the contraindications for Fibrates (fenofibrate/Gemfibrozil)?

A
  • Use w/ Caution in Pt’s with Biliary Tract Dz or in those w/ high risk (women, native Americans, the obese) due to increased risk of cholelithiasis
  • Myopathy and Rhabdomyolysis (when combined with statins)
  • Fibrates may potentiate the action of anticoagulants
  • Fibrates should be avoided in Pt’s with hepatic or renal dysfunction
  • Safety not establish for us in women/pregnant women
30
Q

What are the 3 Bile Acid Sequestrants (Resins) we discussed?

A

Cholestyramine
Colesevelam
Colestipol

31
Q

Explain the Pharmacokinetics of Bile Acid Sequestrants (Resins)?

A

Resins are large polymeric cationic compounds that are completely insoluble in water and are neither absorbed nor metabolic altered in the intestine and are totally excreted in the feces

32
Q

What is the mechanism of action of Resins (Bile Acid Sequestrants)?

A

Resins are positively charged and will bind to the negatively charged Bile Acid (metabolites of Cholesterol) and Increase their excretion up to tenfold.

  • > enhances conversion of Cholesterol->Bile Acids in Liver by 7a-Hydroxylation (no negative FB from BA)
  • > decreased Hepatic cholesterol -> increased hepatic LDL Receptor expression -> increased Hepatic LDL uptake -> decrease in LDL levels
33
Q

Why is it most useful to use a Statin alongside a Resin?

A

Resin’s effect of increasing Hepatic LDL uptake -> decreased LDL levels is partially offset by a Hepatic up-regulation of HMG-CoA Reductase.

Using a statin alongside a Resin will prevent this up-regulation and increase. The effectiveness of a Resin

34
Q

What are the clinical uses of Resins (Bile Acid Sequestrants)

A

Resins may be used to treat:

  • Pt’s with Primary Hypercholesterolemia
  • Type IIa or IIb Hyperlipidemias (alone or with Niacin)
  • to relieve Pruritis in Pt’s who have bile salt accumulations (i.e. biliary obstruction)
35
Q

What are the adverse effects of Resins?

A
  • GI Sx: constipation, nausea, flatulence are most common
36
Q

What are some of the Contraindications of Resins?

A
  • High doses impair fat-soluble Vitamin absorption (ADEK)
  • Impairs Absorption of numerous drugs (tetracycline, phenobarbitol, digoxin, Warfarin, Pravastatin, Fluvastatin, Aspirin, and thiazides diuretics), Thus any additional meds (except Niacin) should be given 1 hr before or 2 hours after.
  • Use caution in Pt’s with diverticulitis, pre-existing bowel disease, or cholestasi
37
Q

What is the first and only approved Cholesterol Absorption Inhibitor?

A

Ezetimibe

38
Q

Describe the Pharmacokinetics of Ezetimibe?

A

Ezetimibe, the Cholesterol Absorption Inhibitor, is highly water insoluble, mostly excreted through feces, and has a half-life of 22hrs

39
Q

What is the Mechanism of Action of Ezetimibe?

A

Ezetimibe selectively inhibits Intestinal Absorption of Cholesterols and Phytosterols (plant sterols); it is thought to inhibit the transporter NPC1L1; effective even without high dietary cholesterol as it inhibits the reuptake of cholesterol excreted as bile. It lowers LDL and TG’s and only slightly raises HDL

40
Q

What are the clinical uses of Ezetimibe?

A

Ezetimibe is used to treat:

  • primary Hypercholesterolemia (alone or with an HMG-CoA Reductase Inhibitor)
  • Homozygous Familial Hypercholesterolemia
  • Mixed Hyperlipidemia
41
Q

What contraindications and adverse effects are there for Ezetimibe?

A
  • no significant drug interactions have been reported

- Use of Bile Acid Sequestrants (resins) should be avoided concomitantly though

42
Q

What is the MOA of Lomitapide?

A

Lomitapide directly binds to and inhibits Microsomal Triglyceride Transfer Protein (MTP) located the in ER cytoplasm.

MTP inhibition prevents the assembly of apo-B containing lipoproteins in enterocytes and hepatocytes -> Decreased production of chylomicrons and VLDL -> subsequently reduces plasma LDL-C

43
Q

What are some of the adverse effects and Contraindications of Lomitapide?

A
  • Lomitapide is a substrate and inhibitor of CYP3A4 causing interactions with a number of other drugs
  • GI symptoms are most common adverse effects
  • increased Liver aminotransferase levels
  • Hepatic fat accumulation
44
Q

What is the MOA of Mipomersen?

A

Mipomersen is an antisense oligonucleotide that targets apolipoprotein B-100 mRNA and disrupts its function; apo-B is the ligand that binds LDL to its receptor and is important for the transport and removal of atherogenic lipids

45
Q

What are the adverse effects or contraindications of Mipomersen?

A
  • injection site Rxn (administered via Subcutaneous injection 2x a week)
  • flu-like symptoms, headache
  • elevation of liver enzymes to 3x the upper limit of normal (discontinue if elevation persists or symptoms develop)
46
Q

What is the MOA of PCSK9 Inhibitors?

A

Antibodies bind to PCSK9 and inhibit LDL Receptor metabolism; results in LDL reductions up to 70%

47
Q

What are the restrictions in giving patients PCSK9?

A

Patients receiving PCSK9 must have Familial Hypercholesterolemia or clinical atherosclerotic CV disease who require additional reduction of LDL. They are given with diet and maximal tolerated statin and/or Ezetimibe

CPR Exam 1 (9 decks)

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