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*Pharm Exam 4 > Hyperlipidemia Drugs > Flashcards

Hyperlipidemia Drugs Flashcards

1
Q

What is the most important function of HDLs?

A

They promote reverse cholesterol transport (transport of cholesterol from periphery back to liver, where it can be secreted as bile).

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2
Q

HDLs inhibit the oxidation of LDLs via _____ enzyme.

A

paraoxonase (PON1)

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3
Q

What are optimal serum lipid levels?

A
  • total cholesterol: <200
  • LDL: <100
  • HDL: >40 M, >50 W
  • TG: <150
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4
Q

What is considered to be very high/too high for LDL and TG levels?

A

LDL above 190 mg/dL and triglycerides above 500 mg/dL

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5
Q

What is the primary drug target in hyperlipidemia treatment?

A

decreasing LDL (w/ statins, bile acid-resins, cholesterol absorption inhibitors, and PCSK9 inhibitors)

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6
Q

What are the secondary targets of hyperlipidemia treatment?

A

increasing HDL and decreasing triglycerides

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7
Q

Why is exercise/weight reduction beneficial for patients with hypercholesterolemia?

A

It improves lipoprotein metabolism.

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8
Q

What are the drug classes that principally reduce LDL levels?

A
  • Statins
  • Bile acid-binding resins
  • Cholesterol absorption inhibitors
  • PCSK9 inhibitors
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9
Q

Most commonly prescribed after the statins and often used in combo with the statins:

A

cholesterol absorption inhibitors

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10
Q

MOA of the statin drugs?

A

They are competitive inhibitors of HMG-CoA reductase, as they are structural analogs of HMG-CoA and therefore substrates for HMG-CoA reductase (the rate limiting step in cholesterol biosynthesis).

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11
Q

What is the most important regulator of the LDLR gene?

A

SREBP transcription factor (leads to increased expression of LDLR at plasma membrane, therefore increased clearance of serum LDL).

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12
Q

True or false: Statins exert a dose-dependent effect in terms of their efficacy.

A

False! Doubling the statin dose usually results in a modest decrease in LDL while significantly increasing the potential for adverse effects.

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13
Q

What is the most serious adverse effect to keep in mind with statin use?

A

They have the potential to cause rhabdomyolysis, which is a rare but very serious complication.

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14
Q

What is a common but less serious adverse effect of statins?

A

myalgia (pain) and myopathy (weakness)

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15
Q

When is the risk of rhabdomyolysis with statin use the greatest?

A

when high statin doses are used, or when there are drug interactions (esp. inhibitors of CYP3A4)

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16
Q

Fewer muscular adverse effects have been observed with which statin?

A

pravastatin

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17
Q

Statins are directly take up into the liver via:

A

organic anion transporter 2 (OATP2); this explains the dominant effect of statins in the liver

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18
Q

What are the main drug interactions to worry about with the statins?

A

CYP450 enzyme inhibitors, which will increase the concentration of statins and lead to increased risk of adverse effects (esp. myopathy and rhabdomyolysis)

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19
Q

What are some of the well-known CYP3A4 inhibitors that may affect statin metabolism?

A

cyclosporin, ritonavir, itraconazole, erythromycin

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20
Q

What is the statin of choice when drug interactions are a concern? Why?

A

Pravastatin because it is NOT metabolized by P450 enzymes. It is the only statin FDA-approved for use with cyclosporin!

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21
Q

Only statin that is FDA-approved for use with cyclosporin?

A

pravastatin

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22
Q

Strongly associated with an increased risk of statin-induced myopathy and rhabdomyolysis due to inhibition of OATP2 transporter and inhibition of glucuronidation:

A

Gemfibrozil (a fibrate drug)

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23
Q

Which drug can cause an increase in the systemic levels of ALL statin drugs, including pravastatin?

A

Gemfibrozil (a fibrate drug)

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24
Q

What is a new concept in statin therapy that may prevent disease at an earlier age?

A

earlier, more aggressive therapy (this may delay the formation of fatty streak lesions)

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25
Q

What are the contraindications of statins?

A
  • Pregnant women, nursing mothers, and women who may become pregnant (Category X - inhibition of cholesterol synthesis may adversely affect fetus)
  • Patients with liver disease (due to predominant hepatic elimination) - pravastatin=safer choice
26
Q

MOA of bile acid-binding resins?

A

Resins are cationic polymers that bind to negatively charged bile acids and prevent their reabsorption in the small intestine. Decreased bile acid reabsorption causes increased bile acid synthesis in the liver (cholesterol converted to bile acids), resulting in decreased hepatic cholesterol. This triggers up-regulation of LDLR and increased LDL clearance.

27
Q

What is an unintended consequence of bile acid-binding resins?

A

Bile acids normally serve to suppress endogenous TG synthesis; thus, bile acid resins can cause an increase in triglyceride levels (especially in patients with hypertriglyceridemia/type III dysbetalipoproteinemia)

28
Q

Contraindications for resins?

A

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

29
Q

Describe 2 instances in which resins are useful in combination with statins.

A
  • to aggressively reduce LDL if a statin is not sufficient (additive effect)
  • to allow use of a lower statin dose in order to avoid statin-dependent adverse effects
30
Q

In a pregnant or lactating women who needs pharmacologic intervention for hypercholesterolemia, which agent is the best choice?

A

a bile acid-binding resin

31
Q

Why are resins so safe to use?

A

because they are not absorbed or metabolized, so they have few side effects

32
Q

Do resins interact with many drugs?

A

Yes, they interfere with the absorption of many drugs (ex: warfarin, phenobarbital, digoxin, tetracycline, thiazide diuretics). Therefore, these drugs should be taken 1-2 hrs before or 4-6 hrs after resins.

33
Q

Which drug is an inhibitor of cholesterol absoprtion?

A

ezetimibe

34
Q

MOA of ezetimibe?

A

inhibits the action of NPC1L1 involved in the absorption of dietary/biliary cholesterol, thereby decreasing hepatic cholesterol, increasing LDLR expression, and increasing LDL clearance

35
Q

Most widely prescribed LDL lowering drug after statins:

A

ezetimibe

36
Q

Is ezetimibe better used as a monotherapeutic agent or in combination with another drug class?

A

often used in combo with a statin drug due to only having a modest effect on reducing LDL (further 25% reduction in LDL w/ a statin)

37
Q

Most common adverse effects of ezetimibe?

A

generally well-tolerated, but may cause flatulence and diarrhea

38
Q

True or false: The action of ezetimibe is dependent upon intact LDL receptors.

A

False- ezetimibe can reduce LDL in patients with primary hypercholesterolemia (LDL receptor mutation).

39
Q

How do genetic mutations in PCSK9 affect CVD risk?

A
  • gain of function mutations: increase serum LDL and risk of CVD
  • loss of function mutations: decrease serum LDL and risk of CVD
40
Q

What are the inhibitors of PCSK9 that we should know?

A

alirocumab and evolocumab (human Abs specific for PCSK - injected subQ every 2 weeks)

41
Q

MOA of PCSK9 inhibitors?

A

bind to PCSK9 and prevent its binding to the LDLR, thereby preventing targeting of LDLR to lysosome; this results in increased expression of LDLR at the cell surface, promoting enhanced LDL clearance

42
Q

Responsible for tonically controlling levels of LDLR expressed on liver cells:

A

PCSK9 (the amount of PCSK9 determines the amount of LDLR expressed on the cell surface)

43
Q

_______ promotes a decrease in serum LDL even in the presence of maximally tolerated statin drugs.

A

alirocumab (a PCSK9 inhibitor)

44
Q

What aspect of PCSK9 inhibitors prevents widespread use of this class?

A

high cost

45
Q

These drugs have a black box warning for hepatotoxicity:

A

Lomitapide and Mipomersen

46
Q

Serum triglyceride levels above 500 mg/dL are a risk factor for:

A

pancreatitis

47
Q

Which drugs are effective in the treatment of homozygous familial hypercholesterolemia (FH)?

A

Lomitapide and Mipomersen

48
Q

Which drugs are used in the treatment of hypertriglyceridemia?

A

niacin or fibrates (gemfibrozil and fenofibrate)

49
Q

What is the initial goal in treatment of hypertriglyceridemia?

A

to prevent pancreatitis by lowering TG levels with niacin or a fibrate; then, LDL goals should be addressed

50
Q

Most effective drug at raising HDLs?

A

niacin

51
Q

What is important to know about the MOA of niacin?

A

It is complex and evolving!

52
Q

Niacin reduces the level of _____.

A

Lp(a) lipoprotein (a modified form of LDL that is covalently linked to the Lpa protein; it is homologous to plasminogen and inhibits tPA/uPA to block the formation of plasmin).

53
Q

What are the main contraindications associated with niacin?

A
  • patients w/ peptic ulcer disease (related to GI stress)

- patients w/ a Hx of gout (inhibits tubular secretion of uric acid)

54
Q

What are the main adverse effects of niacin?

A

skin flushing and itching (pruritis) - prostaglandin-mediated and can be diminished by prior treatment with an NSAID

55
Q

What are some of the proposed MOAs of niacin?

prob. not as impt.

A
  • reduces level of Lp(a), thereby increasing plasmin and thus fibrinolysis (this decreases risk of clot formation and stroke/MI)**
  • agonist for GPCR expr. in adipose tissue, which inhibits cAMP-induced lipolysis and therefore reduces release of FFAs
  • inhibitor of DGAT, thus reducing hepatic VLDL synthesis
  • reduces hepatic expr. of apoCIII, leading to incr. LPL activity and incr. VLDL clearance
  • increaes HL of apoAI, resulting in incr. serum conc. of HDLs
  • inhibitor of foam cell formation
56
Q

MOA of fibrates?

A

act as ligands for PPARα, thereby activating it and promoting expression of genes involved in lipoprotein structure, function, and metabolism

57
Q

Main clinical indication for fibrates?

A

treatment of hypertriglyceridemia associated with low HDL (decrease serum triglycerides and increase HDL levels)

58
Q

What is the therapy of choice for patients with familial dysbetalipoproteinemia/type III hyperlipoproteinemia?

A

fibrates

59
Q

Main adverse effects of fibrates?

A
  • increased predisposition to gallstones

- myopathy and rhabdomyolysis leading to acute renal failure (VERY rare)

60
Q

Main contraindications for fibrates?

A
  • patients with severe renal dysfunction (bc fibrates are renally excreted; renal failure can cause significant elevation of fibrates)
  • patients with pre-existing gallbladder disease (due to effects of fibrates on cholesterol excretion)
61
Q

Reason why fibrates interact with other drugs, including anti-coagulants and sulfonylureas?

A

They are strong protein binders and can displace other protein-bound drugs from albumin, resulting in increased concentrations.

  • warfarin: increased bleeding
  • sulfonylureas: increased risk of hypoglycemia
62
Q

Which fibrate is the drug of choice for combo therapy with statins?

A

fenofibrate (gemfibrozil can cause incr. conc. of statins leading to incr. risk of rhabdomyolysis)

*Pharm Exam 4 (12 decks)

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