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Pharmacology > Hyperlipidemia Drugs > Flashcards

Hyperlipidemia Drugs Flashcards

1
Q

What are the normal levels of LDL?

A

Less than 100 mg/dL

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2
Q

What are the normal levels of HDL?

A

Greater than 40 mg/dL for Men

Greater than 50 mg/dL for Women

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3
Q

What are the normal levels of triglycerides?

A

Less than 150 mg/dL

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4
Q

Hyperlipidemia

A

Abnormal/elevated levels of cholesterol/triglycerides in blood

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5
Q

What has a direct relationship with CHD?

A

LDL levels

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6
Q

What can elevated triglycerides cause?

A

Pancreatitis

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7
Q

LDL Lipoprotein

A

Made of apolipoprotein B100 outside with triglyceride and cholesterol esters on the inside

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8
Q

What is the function of LPL?

A

Cleaves off FFAs from triglycerides for adipose tissue or for use in the muscle

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9
Q

How does increased LDL levels cause atheroscleroisis?

A
  1. Endothelial injury allows for the entry of LDL
  2. LDLs are oxidized to OxLDLs
  3. Activated endothelium with adhesion proteins allows monocyte entry and differentiation to macrophages
  4. Phagocytosis of OxLDLs
  5. Macrophages become FOAM cells that once undergo necrosis, release cholesterol and lead to the formation of a fatty streak
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10
Q

What is the protective function of HDLs?

A
  • Inhibit the oxidation of LDLs
  • Inhibit the expression of adhesion molecules on the endothelium
  • Promote reverse cholesterol transport
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11
Q

What levels of LDL and triglycerides are considered VERY HIGH?

A

LDL - Greater than 190

TG - Greater than 500

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12
Q

What are the drugs that lead to the decrease in LDL levels?

A

Statins
Bile acid-resins
Chol. Absorption Inhibs
PCSK9 inhibitors

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13
Q

What are the drugs that lead to the decrease in TG levels and increase in HDL levels?

A

Niacin

Fibrates

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14
Q

What is the drug of choice in treating hypercholesterolemia?

A

Statins

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15
Q

What is the primary clinical effects of statins?

A

Significant reduction in LDL-cholesterol (20-60%- dose/drug specific)

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16
Q

What are the other effects of the statins on the HDL and TGs?

A
  • Modest reduction in triglycerides (10-20%)

* Modest increase in HDL (5-10%)

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17
Q

Statin MOA

A

Statins competitively inhibit HMG-CoA reductase - inhibit endogenous cholesterol synthesis and reduced hepatic cholesterol synthesis triggers a signaling pathway that induces the activation of the SREBP transcription factor.

SREBP will increase LDL-R synthesis and increase LDL uptake into the liver.

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18
Q

What are some other actions of statins that make them good for treatment of atherosclerosis?

A
  • Decrease FOAM cell formation
  • Inhibit inflammatory responses
  • Stabilize endothelium
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19
Q

What are the main indications of statins?

A
  1. The drugs of choice for treating patients with increased LDL-C
  2. Drugs of choice for both primary and secondary prevention of CHD (even for those with normal LDL)
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20
Q

Should statin doses be doubled to increase effects?

A

NO as it significantly increases the adverse effects as well

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21
Q

Statin SE

A
  • Myopathy
  • Myalgia
  • Rhabdomyolysis
  • Small increase in diabetes risk
  • GI disturbances
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22
Q

When does rhabdomyolysis with statins generally occur?

A

Occurs primarily at high statin doses or due to drug interactions (cyclosporin/macrolides)

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23
Q

Which of the statins undergo CYP3A4 metabolism?

A

Lovastatin, Simvastatin, Atorvastatin undergo metabolism by CYP3A4

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24
Q

Which of the statins undergo CYP2C9 metabolism?

A

Fluvastatin and Rosuvastatin (also in 2C19)

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25
Q

What is the liver transporter that takes up statins?

A

OATP2

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26
Q

What is the bioavailability of statins?

A

Low. Systemic bioavailability is only 5-30% of the administered dose

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27
Q

What is the main site of metabolism and excretion of the statins?

A

They are metabolized in the liver and excreted in the bile and feces

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28
Q

What statin is not metabolized by CYP450 enzymes and has dual renal/hepatic excretion?

A

Pravastatin

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29
Q

How do statins interact with drugs that inhibit CYP450 enzymes?

A

Drugs that inhibit cytochrome P450 enzymes will increase the concentration of specific statins leading to increased risk of adverse effects especially myopathy and rhabdomyolysis

30
Q

What is the only statin approved for use with cyclosporin in transplant patients?

A

Pravastatin

31
Q

What can interactions with statins by gemfibrozil cause?

A

It is strongly associated with an increased risk of statin-induced myopathy and rhabodmyolysis.

32
Q

What are the 2 mechanisms of drug interaction of gemfibrozil with statins?

A
  1. It inhibits OATP2 transporter-mediated uptake of statins

2. It inhibits the glucoronidation of statins which is involved in the metabolism of ALL statins

33
Q

Statin Contraindications

A
  • Pregnancy
  • Nursing
  • Patients with liver disease due to hepatic elimination
34
Q

What is the primary clinical effect of bile acid binding resins?

A

• Modest reduction in LDL-C (10-25%)

35
Q

How can bile acid binding resins affect TGs?

A

Can potentially cause a small increase in serum triglycerides

36
Q

Bile Acid Binding Resin MOA

A

Resins are cationic polymers that bind to negatively charged bile acids and prevent their reabsorption in the small intestine.

Decreased bile acid resorption causes increased bile acid production in the liver resulting in a decrease in the hepatic cholesterol concentration which triggers upregulation of LDL-R and increased LDL clearance.

37
Q

What happens to 7α-hydroxylase in patients on bile acid binding resins?

A

Decreased bile acid resorption upregulates cholesterol α-hydroxylase, the rate limiting enzyme in bile acid synthesis resulting in increased conversion of cholesterol to bile acids

38
Q

What are the uses of bile acid binding resins?

A
  • 2nd line use to reduce CHD
  • Combination with statins to reduce statin dose and minimize SE
  • Drug of choice for treating hypercholesterolemia in children & women who are lactating, or pregnant
39
Q

Bile Acid Binding Resin SE

A

Resins not absorbed or metabolized- therefore very safe/few side effects

40
Q

What are the drug interactions of bile acid binding resins?

A

At high concentrations Cholestyramine and Colestipol, but not Colesevelam, impair the absorption of the fat soluble vitamins A, D E & K and absorption of many drugs:
tetracyline, penicillin, vancomycin, phenobarbital, digoxin, warfarin, propanalol, parvastatin, fluvastatin, aspirin, and thiazide diurectics

41
Q

Bile Acid Binding Resin Contraindications

A

Type III Dysbetalipoproteinemia and raised triglycerides (>400 mg/dL) due to risk of further increasing VLDL levels

42
Q

Inhibitors of Cholesterol Absorption Clinical Effects

A
  • Reduces LDL-C (~18%)

* Minimal effect on HDL and triglycerides (does NOT raise TG levels)

43
Q

Inhibitors of Cholesterol Absorption MOA

A

Inhibits the action of the Niemann-Pick C1-like 1 protein (NPC1L1) involved in the absorption of dietary and biliary cholesterol in the small intestine.

Reduced cholesterol absorption results in the decreased delivery of cholesterol to the liver, thereby reducing VLDL and LDL production and increasing LDLR.

44
Q

What are the clinical uses of Inhibitors of Cholesterol Absorption?

A
  1. Reduces LDL-C in patients with primary hypercholesterolemia - not solely dependent on in tact LDL-R
  2. Can induce a significant further LDL-C lowering effect when combined with a STATIN
45
Q

Inhibitors of Cholesterol Absorption SE

A

Generally well tolerated

- Flatulence and Diarrhea the most common effects

46
Q

What is PCSK9 and what are its functions?

A

PCSK9 is a secreted enzyme produced by the liver & other cell types

  • Binds to the LDLR at the cell surface and is internalized with the receptor and LDLs
  • Prevents LDLR recycling back to the plasma membrane and instead targets the receptor to degradation in the lysosome
47
Q

Inhibitors of PCSK9 MOA

A

Antibodies against PCSK9

  • bind to PCSK9 and prevent its binding to the LDLR
  • thereby prevent the targeting of LDLR to the lysosome
  • result in increased expression of LDLR at the cell surface
48
Q

Lomitapide MOA

A

• Inhibitor of microsomal triglyceride transfer protein (MTP) which is required for the assembly of both chylomicrons & VLDLs - leads to decreased LDLs

49
Q

Mipomersen MOA

A
  • Antisense oligonucleotide specific for apoB100

* Reduces expression of apoB100 resulting in reduced production of VLDLs and hence lower levels of LDLs

50
Q

What are the drugs used to treat hypercholesterolemia?

A
  1. The STATINS
  2. Bile Acid-binding resins
  3. Cholesterol Absorption Inhibitor
  4. PCKS9 inhibitors
  5. Lomitapite and Mipomersen
51
Q

What are the drugs used to treat hypertriglyceridemia?

A

Niacin
Fibrates
Omega-3 Fatty Acids

52
Q

What are the clinical effects of niacin?

A
  • 30-80% reduction in triglycerides
  • 10-20% reduction in LDLs
  • 10-30% increase in HDLs - most effective drug at raising HDLs
53
Q

What are the uses of niacin?

A
  1. Lowers both plasma cholesterol and triglycerides

2. Patients with a previous MI

54
Q

What are some of the actions of niacin (there are many and not to be memorized)?

A
  1. Agonist for Gi-coupled GPCR (GPR109A) expressed in adipose tissue - reduces the release of FFA from adipose tissue
  2. Inhibits DGAT2 - rate limiting enzyme in hepatic triglyceride synthesis - reduces hepatic VLDL synthesis
  3. Reduces hepatic expression of apoCIII (secreted inhibitor of LPL) - leads to increased LPL activity
    - resulting in increased VLDL clearance
  4. Increases the half life of apoAI - the major lipoprotein present in HDLs - increases concentration of serum HDLs - promotes reverse cholesterol transport
  5. Inhibits macrophage recruitment to atherosclerotic lesions (via activation of GPR109A)
55
Q

What are the effects of niacin on thrombolysis?

A

Increases Thrombolysis
Decreases Risk of clots
Decreased Risk of MI/Stroke

56
Q

Niacin SE

A
  1. Skin flushing and itching (pruritis) - prostaglandin-mediated effect
  2. Inhibits tubular secretion of URIC ACID- predisposes to GOUT
  3. Can exacerbate PEPTIC ULCER DISEASE
57
Q

Niacin Contraindications

A

a) Peptic Ulcer disease
b) Patients with a history of gout
c) Used with caution in diabetics
d) Used with caution in patients with impaired liver function

58
Q

What is the main clinical effect of fibrates?

A
  • 40-60% reduction in triglycerides
  • Mild (10-20%) reduction in LDL
  • 10-20% increase in HDL
59
Q

Fibrates MOA

A

Fibrates activate nuclear hormone TF PPARα to promote the expression of genes involved in lipoprotein structure, function and metabolism which leads to the increase of plasma HDL and the decrease of plasma triglycerides

60
Q

What are the clinical uses of fibrates?

A
  1. Treatment of hypertriglyceridemia associated with low HDL

2. Treatment of patients with high levels of trigylcerides

61
Q

Fibrates SE

A

Generally well tolerated: Most common side effects are mild GI disturbances

  1. Increased predisposition to gallstones
  2. Myopathy and Rhabdomyolysis leading to acute renal failure (VERY rare) - most often seen with gemfibrozil
62
Q

What are the drug interactions of the fibrates?

A
  1. Both Gemfibrozil and fenofibrate are strong protein binders and can displace other protein-bound drugs from albumin resulting in increased concentrations (i.e. warfarin)
  2. Gemfibrozil can increase the serum concentration of statins leading to an increased risk of myopathy and rhabdomyolysis
63
Q

Fibrates Contraindications

A
  1. Pregnant/lactating women or women who may become pregnant
  2. Patients with severe hepatic or renal dysfunction
  3. Patients with pre-existing gallbladder disease
64
Q

What is the primary clinical effect of omega-3 fatty acids?

A
  • Lowers serum TG levels by ~30-50%
  • Minor increase in HDL
  • Can increase LDL in some individuals
65
Q

What is the therapeutic use of omega-3 fatty acids?

A

Currently approved only as an adjunct to diet in the treatment of hypertriglyceridema in individuals with trigylceride levels >500 mg/dl

66
Q

Omega-3 FA MOA

A

Appears to involve inhibiting the expression of genes involved in hepatic triglyceride synthesis - also has anti-inflammatory effects

67
Q

What are some of the statins?

A 
Atorvastatin 
Fluvastatin
Lovastatin
Simvastatin 
Pravastatin 
Rosuvastatin
68
Q

What are some of the bile acid binding resins?

A

Cholestyramine
Colestipol
Colesevelam

69
Q

What is a cholesterol absorption inhibitor?

A

Ezetimibe

70
Q

What are the PCKS9 inhibitors?

A

Alirocumab

Evolocumab

71
Q

What are the drugs to treat homozygous Familial Hypercholesterolemia?

A

Lomitapide

Mipomersen

72
Q

What are the fibrates?

A

Fenofibrate

Gemfibrozil

Pharmacology (74 decks)

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