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PHARM/MHD - Exam #4 > Pharm - Lec#3 - Hyperlipidemia &TG drugs > Flashcards

Pharm - Lec#3 - Hyperlipidemia &TG drugs Flashcards

1
Q

What drugs are in the STATIN drug class?

A
  1. Lovastatin
  2. Simavastatin
  3. Atorvastatin
  4. Fluvastatin
  5. Rosuvastatin
  6. Pravastatin
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2
Q
  1. Lovastatin
  2. Simavastatin
  3. Atorvastatin
  4. Fluvastatin
  5. Rosuvastatin
  6. Pravastatin

Indication?
MOA?

A

A) Indicated for HIGH LDL

B)
Inhibits HMG - Co A reductase & triggers SREBP transcription factor

leading to:

  1. increased LDL -R expression
  2. increased LDL clearance from the plasma!
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3
Q

Statins affect on serum lipids (LDL, TG, HDL)

  1. Lovastatin
  2. Simavastatin
  3. Atorvastatin
  4. Fluvastatin
  5. Rosuvastatin
  6. Pravastatin
A 
LDL decreased (20-60%)
TG decreased (10-20%)
HDL increased! (5-10%)
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4
Q

What is the MAJOR adverse reaction of Statins? (3 other adverse effects)

  1. Lovastatin
  2. Simavastatin
  3. Atorvastatin
  4. Fluvastatin
  5. Rosuvastatin
  6. Pravastatin
A

RHABDOMYOLYSIS!

  1. muscle myalgia/myopathy
  2. Hepatitis
  3. Small risk of Type 2 diabetes
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5
Q

What is the major contraindication for statins?

A

SEVERE LIVER DISEASE

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6
Q

What are some drug interactions for statins? (4)

A
  1. CYP3A4 inhibitors
    (increase L, S, A )
    increased risk of adverse effects!!!
    - erythromycin, cyclosporine, ketaconazole, HIV pro inhibittors & GRAPEFRUIT juice
  2. CYP3A4 inducers (decrease L, S , A)
    - DECREASED CLINCIALY EFFICACY!
    - pheynotin, phenobarbital, rifampin
  3. CYP2C9 inhibitors
    (increase E, R)
    - ketoconazole, metronidazole
  4. GEMFIBROZIL
    - decrease OATP2, decrease glucoronidation= increase all statins
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7
Q

What are the 3 bile acid binding resins?

A

Cholestryramine
Colestipol
Colesevelam

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8
Q

Bile Acid Resins:
Cholestryramine
Colestipol
Colesevelam

Indication?

MOA?

A

Indication: High LDL

MOA: binds bile acids and PREVENTS reabsorption–> increases 7a-hydroxylase –> decrease cholesterol –> increase LDL - R –> INCREASE LDL CLEARANCE!

when more 7a-hydroxlase = more bile acids made and less cholesterol!

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9
Q

Bile Acid Resins:
Cholestryramine
Colestipol
Colesevelam

Effects on LDL?

adverse effect?

Contraindication?

A

DECREASE LDL (10-25%)

  1. Adverse effect: can increase TG LEVELS IN HYPERTRIGLYCERIDEMIA
  2. CONTRAINDICATED:
    TG> 400 mg/dL

due to risk of further increasing VLDL levels!!!
(TEST)

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10
Q

What two bile acid resins interfere with the absorption of drugs like warfarin, phenobarbital, digoxin, and tetracycline?

A

Cholestyramine/ Colestipol

At high concentrations Cholestyramine and Colestipol, but not Colesevelam,
impair the absorption of the fat soluble vitamins A, D E & K

& tetracyline, penicillin, vancomycin, phenobarbital, digoxin, warfarin,
propanalol, parvastatin, fluvastatin, aspirin, and thiazide diurectics

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11
Q

Ezetimibe:

  1. Indication?
A

Indication high LDL
- primary hypercholesterolemia!!!

Ezetimibe: Therapeutic Uses
Reduces LDL-C in patients with primary hypercholesterolemia
- i.e. not completely dependent upon intact LDLR

  1. Can induce a significant further LDL-C lowering effect when combined
    with a STATIN
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12
Q

Ezetimibe: Effect on serum lipids

Adverse effects?

A

LDL decrease (18%)

NONE - flatulence& diarrhea

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13
Q

Ezetimibe

2. MOA?

A

MOA: inhibits intestinal absorption of cholesterol (via NPCL1)

  • -> decrease hepatic cholesterol
  • -> increase LDL - R expression
  • -> INCREASE LDL CLEARANCE!

____________

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

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

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14
Q

Niacin:

Indications? (3)

Clinical effect?

A
  1. High VLDL
  2. High LDL
  3. Low HDL

TG - 30-80% reduction in triglycerides
LDL - 10-20% reduction in LDLs
HDL - 10-30% increase in HDLs - most effective drug at raising HDLs!!

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15
Q

What is the most effective drug at raising HDLs?

A

Niacin

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16
Q

MOA of Niacin

5

A
  1. Adipocytes
    - decreased lipolysis in adipocytes–> decreased FFA –> decreased VLDL
    • inhibits DGAT2 which results in decreased VLDL synthesis
  3. inhibit ApoCIII –> which usually inhibits LPL –> thus increase in LPL–>
    increased VLDL clearance
  4. Increased apoAI expression –> increased HDL production
  5. decreased Lp(a) –> decreased
    Thrombosis

(Lp(a) is homologous to plasminogen - Lp(a) blocks the formation of plasmin and prevents thrombolysis, thereby increasing the risk of a CLOT forming)

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17
Q

What are the 3 main adverse effects of Niacin?

2 others

A
  1. SKIN FLUSHING (tx: NSAID - COX inhibitor to decrease prostaglandin production)
  2. RISK OF GOUT
  3. EXACERBATES PEPTIC ULCERS
  4. Risk of hyperglycemia
  5. Hepatitis
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18
Q

What are the 2 fibrates?

A
  1. Gemfibrozil

2. Fenofibrate

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19
Q

What is the indication for fibrates: (Gemfibrozil, Fenofibrate)

Effect on serum lipids?

A
  1. High VLDL
  2. Low HDL
  3. decrease TG (40-60%)
  4. decrease LDL (10-20%)
  5. Increase HDL (10-20%)
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20
Q

What is the MOA of fibrates

Gemfibrozil, Fenofibrate

A

LIGANDS FOR PPAR alpha TF

  1. decrease ApoC3 and increase LPL expression, increasing fatty acid oxidation
    - decreased VLDL synthesis
    - increased VLDL clearance
  2. Increase APOI expression
    - increased HDL production
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21
Q

What are the 2 main adverse effects of Fibrates?

2 others?

Contraindicated? (2)

A
  1. Increased GALLSTONES! (test)
  2. Rhabdomyolysis
  3. Hepatits
  4. Myopathy

Contraindication in severe renal/hepatic disease

22
Q

What are some drug interactions of Gemfibrozil & fenofibrate? (2- 2nd is especially true for gemfibrozil)

What type of drugs are these?

A
  1. Strong protein binders:
    - increase warfarin & risk of bleeding
    - - increased sulfonylureas and hypoglycemia

2.Statin interaction:
- inhibit OATP2 / glucoronidation
- increased STATINS and rhabdomyolysis
ESPECIFALLY GEMFIBROZIL

23
Q

What two drugs are PCSK9 inhibitors?

A

Alirocumab

Evolocumab

24
Q

Alirocumab
Evolocumab
(PCSK9 inhibitors)

Indications?

A
  • hetero Familial Hypercholesterolemia
  • High LDL not controlled with maximum STATIN or STATIN intolerant!
  • 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
    • approved for treatment of heterozygous FH & patients that
      have not achieved goals with maximally tolerated STATINs
25
Q

MOA of Alirocumab

Evolocumab

A

(PCSK9 inhibitors)

Inhibits PCSK9 –> blocks normal targeting of LDLR to lysosome

  • increased LDL-R expression and increased LDL clearance
26
Q

Effect of PCSK9 inhibitors on serum lipids ( alirocumab, Evolocumab)

A

decreased LDL (>50%)

27
Q

What drug (s) is indicated for homozygous familiar hypercholesterolemia?

A

Lopitapide

Mipomersen

28
Q

MOA of Lopitapide

A

inhibits MTP in both enterocytes and liver

  • decreased production of chylomicrons, VLDL, and LDL

Inhibitor of microsomal triglyceride transfer protein (MTP)
MTP is required for the assembly of both chylomicrons & VLDLs
Since chylomicrons and VLDLs give rise to LDLs LOMITAPIDE can reduce LDL levels in FH patients

29
Q

Lopitapide: effect on serum lipids

A

decreased:

chylomicrons, VLDL, LDL

30
Q

Lopitapide:

Adverse effects/ contraindication

Drug interactions?

A

HEPATOTOXICITY

  • contraindicated in PREGNANCY!!
    2. CYP3A4 and P-gp inhibitor
  • many drug interactions
31
Q

Mipomersen

  • indication
  • MOA
A

Indication: Homozygous FH (like lopitamide)

MOA?
- antisense oligonucleotide specific for apoB100

  • Reduces expression of ApoB (100 & 48) resulting in reduced production of VLDLs and hence lower levels of LDLs
32
Q

Mipomersen: effect on serum lipids

A

decreased VLDL

decreased LDL

33
Q

Mipomersen:

Adverse effect

contraindication

A
  1. Hepatoxocity

Contrindicated: mild/moderate HEPATIC impairment

34
Q

Which 3 drugs are contraindicated in SEVERE liver disease?

A
  1. Statins
  2. Fibrates
  3. Mipomersen

(lipotamide & mipomersen can both use severe LIVER toxicity)

35
Q

What are the accepted values for desirable, borderline, and high

  1. cholesterol
  2. LDL
A

Cholesterol:
high: 240 mg/dL

LDL:
high 190 mg/Dl

(borderline 130-159)

36
Q

What are the accepted values for desirable and high

  1. HDL
  2. TG
A

HDL:
M> 40 mg/dl
W> 50 mg/dl

TG:
very high: 500 mg /dL

37
Q

Severe hypercholesterolemia drug therapy indicated for:

what LDL levels?

With diabetes?

A
  1. LDL >190 md/dl
  2. or >70 md/dl in diabetes

the initial goal is to reduce LDL - risk of atherosclerosis

  • the initial drug of choice is typically a STATIN
38
Q

What drugs would be used to treat hypercholesterolemia?

A

STATINS

Bile Acid Binding Resins

Cholesterol Absorption Ihbitiors (ezetimibe)

PCSK9 inhibitors:
Evolocumba
Alirobumab

39
Q

What drugs would be used to treat hypertrygliceridemia?

A

Fibrates

(gemfibrozile, fenofibrate)

or NIACIN

40
Q

Homozygous Familial Hypercholosterolemia is treated with which drugs?

A

Lomitapide & Mipomersen

41
Q

What is the DOC for hyperlipidemia?

A

STATINS

42
Q

Which statin is NOT metabolized by the CYP450 mechanism and is the DOC to use with verapamil, ketoconazole, and macrolide antibiotics (erythromycin)?

A

Pravastatin!

  • thus drugs that inhibit CYP450 (cyclosporin, erythromycin, verapamil, warfarin, ketoconazole) will NOT affect pravastatin

GRAPEFRUIT JUICE also inhibits CYP450

HOWEVER this will affect Lovastatin, SImvastatin & Atorvastatin and result in increased levels of these drugs and RHABDOMYOLYSIS risk!

Phenytoin, griseofulvin, barbiturates, rifampin, thiazolidnediones INCREASE CYP3A4 expression and reduce plasma statins

43
Q

What fibrate inhibits the metabolism of ALL statin drugs by inhibiting statin glucoronidation & statin transporter?

What vibrate is the DOC to be used with statins?

A

GEMFIBROZIL

  • also inhibit OATP2 (statin uptake transporter)
  • increase statin drugs results in rhabdomyolysis
  1. FENOFIBRATE
    - does not affect statin metabolism
44
Q

What are the 3 contraindications of patients taking statins?

A
  1. Pregnant/nursing moms
  2. pts. taking Gemfibrozil
  3. Patients with liver disease
45
Q

Without bile acids, there is no suppression of _____ synthesis

A

Triglyceride!

so the Bile Acid resin drugs ( Cholestyramine, colestipol, colesevelam) which are cationic polymers binding to negatively charged bile acids thus preventing in their reabsorption result in HIGHER TG levels

46
Q

What drug is contraindicated in type II dyslipoproteinemia?

A

BILE ACID RESINS

-increased TG’s –> increased VLDLs –> increased serum TG’s which lead to PANCREATITIS

(cholestyramine, colestipol, colesevelam)

47
Q

___ and ____ inhibit fat soluble vitamins D, A, K,E absorption

A

Cholestyramine & colestipol

  • also interferes with the intestinal absorption of many drugs (tetracycline, digoxin, warfarin etc)
  • NOT colesevelam!
48
Q

What drug when combined with a statin results in an increased LDL lowering?

A

EZETIMIBE

  • bile acids interfere with its absorption
  • cyclosporinincreases its concentration
49
Q

What drugs should not be taken during pregnancy

A
  1. Statins
  2. Ezatimibe
  3. Lomitapide ( drug to treat homozygous familial hypercholesterolemia)
  4. Fibrates (also predispose to gallbladder formation due to increased cholesterol excretion in bile)
50
Q

What is the most affective drug for increasing HDL levels?

What is the therapy of choice for patients with Familial dysbetalipoproteinemia (type III hyperlipoproteinemia)

A

Niacin

- FIBRATES
Fenofibrate, Gemfibrozil

51
Q

FISH oil:

  1. Clinical effect on LDL, HDL, TG
  2. MOA
  3. Clinical use
  4. Adverse
A

1.
increase HDL, decrease TG by 50%, can increase LDL in some people *

  1. MOA: inhibits TG synthesis in liver and increases TG clearance
  2. Adjunct to diet and lifestyle int

PHARM/MHD - Exam #4 (20 decks)

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