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Pharm-Spring > Lipid-Lowering Drugs > Flashcards

Lipid-Lowering Drugs Flashcards

1
Q

Lipoproteins –What is normal physiologic role?

A
  • Triglycerides are an essential energy source
  • Cholesterol is necessary for the production of
    • Cell Membranes
    • Bile Acids
    • Steroid Hormones
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2
Q

What are Lipoproteins?

A
  • Required for transport of lipids to and from cells in periphery.
  • Produced via exogenous pathway (dietary fat, cholesterol, fat-soluble vitamins) or endogenous pathway (synthesis by liver)
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3
Q

Lipoproteins and Density

A
  • Vary in density:
    • Chylomicrons (least dense)
    • Very low density lipoproteins
    • Intermediate density lipoproteins
    • Low density lipoproteins (transport cholesterol out to the body—shuttles to tissues)
    • High density lipoproteins (transport cholesterol back to the liver for removal from circulation)
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4
Q

Why is hyperlipidemia a
problem?

A
  • Hypercholesterolemia
  • Hypertriglyceridemia
  • Elevated LDL
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5
Q

Decreasing LDL’s by ______, can reduce risk of CV event by _____.

A

Decreasing LDL’s by 39 g/dL, can reduce risk of CV event by ~22%.

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6
Q

Primary Hyperlipidemia

A
  • Genetic (or inherited) heterozygous condition resulting in elevated total cholesterol or triglyceride level.
    • Homozygous = rare 4X higher cholesterol levels and much higher atherosclerosis risk
  • Total cholesterol usually > 200, triglycerides often > 500
  • Often referred to as
    • Familial hypercholesterolemia
    • Familial hypertriglyceridemia
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7
Q

Secondary Hyperlipidemia

A
  • Diabetes
  • Hypothyroidism
  • Obstructive liver disease
  • Chronic renal failure
  • Drugs that increase LDL and decrease HDL
    • Progestins
    • Corticosteroids
    • Anabolic steroids
    • Protease Inhibitors (HIV meds)
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8
Q

Total Cholesterol Level

A
  • Desirable < 200 mg/dL
  • Borderline 200-239 mg/dL
  • High > 240 mg/dL
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9
Q

HDL Level

A
  • Low < 40
  • High > 60
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10
Q

LDL Cholesterol

A
  • Optimal < 100
  • Near optimal 100-129
  • Borderline High 130-159
  • High 160-189
  • Very High > 190
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11
Q

Assessing for Atherosclerotic Cardiovascular Disease

A
  • History of coronary heart disease (CHD)
    • Angina
    • Myocardial infarction
    • Coronary interventions (PTCA, Stents, CABG)
  • Peripheral Arterial Disease
    • Peripheral (extremity) arterial disease
    • Symptomatic carotid artery disease
    • Abdominal aortic aneurysm
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12
Q

Atherosclerotic Cardiovascular disease (ASCVD) Risk Factors

A
  • Family history of ASCV, Gender, Age, Race
  • Chronic LDL > 160 mg/dL
  • HDL-Cholesterol
  • SBP
  • Diabetes
  • Smoker
  • Renal disease
  • Metabolic syndrome
  • History of preeclampsia
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13
Q

Intensity of Statin Therapy is based on:

A
  • Presence of Clinical ASCVD
  • Risk of Developing ASCVD
  • Presence of Diabetes +/- hyperlipidemia
  • Presence of isolated hyperlipidemia (genetic component)
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14
Q

High-Intensity Statin Therapy

A
  • Lowers LDL by ≥ 50%
    • Atorvastatin 40-80mg
    • Rosuvastatin 20-40mg
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15
Q

Moderate-Intensity Statin Therapy

A
  • Lowers LDL by 30-49%
    • Atorvastatin 10-20 mg
    • Rosuvastatin 5-10 mg
    • Simvastatin 20-40 mg
    • Pravastatin 40 mg
    • Lovastatin 40 mg
    • Fluvastatin XL 80mg
    • Fluvastatin 40 mg bid
    • Pitavastatin 2-4 mg
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16
Q

Low-Intensity Statin Therapy

A
  • Lowers LDL by < 30%
    • Simvastatin 10 mg
    • Pravastatin 10-20 mg
    • Lovastatin 20 mg
    • Fluvastatin 20-40 mg
    • Pitavastatin 1 mg
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17
Q

High risk patients that might be started on non-statin cholesterol-lowering therapy.

A
  • ASCVD
  • LDL > 190 mg/dL
  • Diabetes
  • Age 40-75
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18
Q

Secondary Treatment Goals

A
  • Treat elevated triglycerides
    • If triglycerides > 200 and LDL goal has been achieved, add additional treatment for TGs
  • Treat low HDLs (<40)
    • If HDLs are < 40 and LDL and TG goals have been achieved, add additional treatment for HDLs
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19
Q

HMG-CoA Reductase Inhibitors

Agents

(3-hydroxyl-3 -Methylglutaryl Coenzyme A Reductase inhibitors)

A
  • Fluvastatin (Lescol)
  • Lovastatin (Mevacor)
  • Atorvastatin (Lipitor)
  • Pravastatin (Pravachol)
  • Simvastatin (Zocor)
  • Rosuvastatin (Crestor)
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20
Q

HMG-CoA Reductase Inhibitors

Mechanism

(3-hydroxyl-3 -Methylglutaryl Coenzyme A Reductase inhibitors)

A
  • “Statins” - Inhibit enzyme (HMG- CoA reductase) that catalyzes rate-limiting step in formation of cholesterol by liver.
    • Specifically, inhibits conversion of HMG-CoA to mevalonate
  • Effect is to:
    • 1) decrease cholesterol synthesis in liver
    • 2) enhance LDL receptor expression which increases LDL uptake by liver
  • Decreases LDLs, decrease TGs, and increase HDLs
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21
Q

HMG-CoA Reductase Inhibitors

Beneficial Effects

(3-hydroxyl-3 -Methylglutaryl Coenzyme A Reductase inhibitors)

A
  • Beneficial for primary & secondary prevention beyond normalization of lipids:
    • Promote plaque stability
      • ↓ cardiac M&M w/periop admin in high risk pt.
    • Antioxidant, anti-inflammatory, vasodilatory
    • RCT show ↓ risk for CV events even w/ normal LDL level
      • ↓heart failure, stroke, MI, hospitalization, PVD, death
      • Helpful in diabetics
    • Increased bone formation
      • May reduce osteoporosis – studies underway
22
Q

HMG-CoA Reductase Inhibitors
PHARMACOKINETICS

A
  • Lovastatin and simvastatin are prodrugs
  • Highly protein bound (except pravastatin)
  • Extensive CYP450 metabolism (except pravastatin)
  • E½t (1-4 hrs) (except atorvastatin – 14 hrs)
    • Clinical effects last for 24 hrs though
23
Q

Adverse Effects of Statins

Common

A
  • Headache
  • Rash
  • GI disturbances
  • Myalgias (up to 1/3 of patients)
24
Q

Adverse Effects of Statins

Rare

A
  • Hepatotoxicity (0.5-2%)
  • Peripheral neuropathy
  • Myopathy/rhabdomyolysis (0.1-0.5%)
    • Fatal rhabdomyolysis < 1 in 1 million
25
Q

Individuals at risk for myopathy

A
  • Pre-existing muscle disease
  • Age > 80,Smallbody frame and frailty,Female, Asian,
  • Hypothyroid
  • Alcohol abuse
  • Impaired renal or hepatic system
  • High statin levels (see drug interactions)
26
Q

Statin Pregnancy Category

A

X

27
Q

Statins: Significant Drug Interactions

A
  • Other Drugs known to induce myopathies: Niacin, Gemfibrozil
  • Cyclosporine increases [] of all statins & r/f myopathy
  • Dabigatran + simvastatin or lovastatin = increase r/f MAJOR hemorrhage
    • (mechanism unclear)
  • The following drugs are CYP3A4 inhibitors, which decrease metabolism of Lovastatin and Simvastatin, increasing their []:
    • Grapefruit juice
    • Itraconazole (Sporanox)
    • Verapamil
    • Amiodarone
    • Cyclosporin
    • HIV protease inhibitors
    • Erythromycin
    • Clarithromycin (Biaxin)
    • Ketoconazole (Nizoral)
28
Q

Drugs to Avoid for Pregnant & Nursing Women

A
  • Statins
  • Ezetimibe
  • Niacin
  • Fibric acid derivatives

Bile acid-binding resins are currently the only lipid-lowering meds safe to use during pregnancy

29
Q

Bile acid sequestrants/resins

Action

A
  • Non-absorbable resin that binds bile acids and other substances in the GI tract preventing absorption and promoting GI excretion.
    • Results in liver using hepatic cholesterol to produce more bile acids and increased LDL receptor expression on hepatocytes.
  • Effect is to decrease LDLs and increase HDLs (little effect on TGs- may actually increase is susceptible patients)
30
Q

Bile acid sequestrants/resins

Agents

A
  • Cholestyramine (Questran)
  • Colestipol
  • Colesevelam
31
Q

Bile Acid Sequestrants

Dosing

A
  • Formulated as a powder mixed with liquid
  • 30 min before, during, or 30 min after meal
32
Q

Bile Acid Sequestrants

Drug Interactions

A
  • Can interfere w/ absorption and/or form complexes w/ many PO meds:
    • Fat soluble vitamins
    • Synthroid
    • Thiazides
    • Oral contraception
    • Phenytoin
    • Sulfonylureas
33
Q

Bile Acid Sequestrants

Adverse Drug Reactions

A
  • Minimal:
    • GI – severe constipation (encourage high fiber diet and adequate hydration), flatulence, N/V
      • Use stool softener
    • Reduced folate levels w/ long-term use
  • Cholestyramine (chloride) can cause hyperchloremic acidosis (young/small pts)
34
Q

Nicotinic Acid (Niacin)

MOA/Effects

A
  • MOA unclear
    • Niacin acts on liver and adipose tissue to inhibit TG production but HDL change remains a mystery
    • Drug of choice in pts at r/f pancreatitis (TG levels)
  • ↓Hepatic synthesis of VLDL by several potential mechanisms (↓ release of FAs), and this leads to a ↓ in LDL and ↓TGs.
  • ↑ HDL levels more effectively than any other drug
    • ↓ HDL breakdown = levels ↑by 20-30mg/L
  • Works by ↓ production of VLDLs. Effect is to ↓ LDLs , ↓ TGs, and ↑ HDLs.
  • *Niacin does little to improve long term outcomes “reduction in risk factors does not translate to reduction in actual risk.”!!
35
Q

Nicotinic Acid (Niacin)

Agents

A
  • Nicotinic acid (Immediate-release, extended-release, and sustained-release or Niaspan)
36
Q

Statin + Niacin =

A

Increased r/f hepatic dysfunction

37
Q

Nicotinic Acid (Niacin)

Adverse Effects

A
  • Skin: intense flushing, itching
    • Can pretreat w/ aspirin 30 min before dose
    • Decreased w/ sustained release version of niacin
  • Vision changes
  • GI: peptic ulcer exacerbation
  • Hyperglycemia
  • Gouty arthritis
  • Can raise blood levels of uric acid (check kidney function, encourage 2-3 L/d water intake)
  • Hepatotoxicity (assess liver function)
38
Q

Nicotinic Acid (Niacin)

Dosing

A
  • Gradually increase dose, extended-release formulations help
    • ASA 30 min prior to admin
    • Cautions: contains yellow dye #5
39
Q

PCSK9 Inhibitors:

Mechanism and Efficacy

A
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that binds to LDL receptors and promotes lysosomal degradation of the receptors.
  • Alirocumab (Praluent) and evolucumab (Repatha) are monoclonal antibodies that bind PCSK9, preventing subsequent binding of PCSK9 to LDL receptors.
  • Result: high [] of LDL receptors = enhanced clearance of LDL-C
  • FOURIER trial: Evolucumab reduced LDL-C
    • Lower risk of MI, CV death, stroke, unstable angina, PCI
  • ODYSSEY trial = when added to statin, reduces death from CV causes
40
Q

↑ HDL levels more effectively than any other drug

A

Nicotinic Acid (Niacin)

41
Q

PCSK9 Inhibitors:

Adverse Effects and Interactions

A
  • Appear well tolerated with no significant interactions
    • Muscle aches, rash, uticaria, mild injection site reactions
  • Abnormally low LDL-C < 25 mg/dL– does not appear to be problematic based on current info
  • May cause neural tube defects – unclear at this time
42
Q

Fibric Acid Derivatives

MOA/Effects

A
  • Interacts w/ a receptor (PPAR alpha), increases synthesis of lipoprotein lipase (LPL), and decreases an apolipoprotein that inhibits LPL = more LPL
  • Increase lipolysis of TG’s (↓ VLDL levels)
    • Most effective drugs available for ↓TG levels (40-50%)
  • Can ↑HDL cholesterol by about 15-25%
  • Very little decrease in LDLs
43
Q

Fibric Acid Derivatives

Agents

A
  • Three drugs in the United States
    • Gemfibrozil (Lopid) – only fibrate associated w/ beneficial CV outcomes
44
Q

Drug of choice in pts at r/f pancreatitis

A

Nicotinic Acid (Niacin)

(TG levels)

45
Q

Fibric Acid Derivatives

Adverse Drug Reactions/Interactions

A
  • Rashes (common)
  • GI disturbances (common)
  • Headache
  • Myopathy & rhabdo –avoid use w/ statins
  • Can increase [] of statins
  • Gallstones (D/C if this occurs and avoid use w/ ezetimibe)
  • Liver injury (hepatotoxic- LTFs)
  • Can potentiate oral anti-hyperglyemic drugs
  • Displaces warfarin from plasma albumin = ↑ r/f bleeding if on warfarin
    • Measure INR frequently
46
Q

Most effective drugs available for decreasing triglyceride levels

A

Fibric Acid Derivatives

47
Q

Combination Therapy:

Statin and Fibric Acid Derivatives

A
  • Primarily assist in decreasing triglycerides
  • Increased risk of myopathies
  • Contraindicated w/ severe hepatic disease
48
Q

Ezetimibe (Zetia) Action

A
  • Works by inhibiting cholesterol and phytosterol absorption from brush border of intestines (disrupts complex between annexin-2 and cavolin-1 proteins). Increases expression of LDL receptors.
    • No effect on absorption of fat soluble vitamins: (A, D, E, K)
    • No apparent effect on CYP450 enzymes
    • Intended for use in combo w/ a statin
49
Q

Ezetimibe (Zetia): Drug interactions

A
  • Ezetimibe…
    • …may increase bleeding risk w/ Warfarin
    • …is increased by and will increase [] of cyclosprorin
    • …when used w/ Gemfibrozil = increased r/f gallstones (combo contraindicated)
    • …absorption inhibited by bile acid sequestrants
50
Q

Ezetimibe (Zetia): Drug interactions

Simvastatin and Ezetimibe (Vytorin)

A
  • More effective than simvastatin alone.
  • IMPROVE-IT trial:
    • Simvastatin + ezetimibe = ↓ LDL.
    • Also ↓ in end point of CV death, major coronary events, or nonfatal CVA
      • Unclear if this is based on overall ↓ of LDL or +ezetimibe but undercuts idea that only statins provide a mortality benefit
51
Q

What’s Next? Apolipoproteins

A
  • The atherogenic lipoprotein particle (LDL, IDL, VLDL, chylomicrons, lipoprotein A) is composed of a core of cholesterol and triglycerides surrounded by the phospholipid membrane with apolipoproteins imbedded within
  • Apolipoproteins necessary for assembly of lipoproteins, provide structural integrity, act as co-activators of enzyme activity, and as receptor ligands for cellular uptake
  • These apolipoprotein particles bind w/ arterial wall and begin oxidative and inflammatory process that encourages atherogenesis
  • Evidence suggests atherogenesis tracks more closely w/ apolipoprotein B (located on VLDL, IDL, and LDL) numbers than w/ LDL or non-HDL numbers
  • Evidence shows that, just as w/↓ in LDLs, ↓ in apolipoprotein B = ↓ CV dz risk
  • Monitoring apolipoprotein B can be useful as additional means of monitoring efficacy of treatment regimen
52
Q

What’s New?

A
  • Mipomersen- Antisense oligonucleotide targeted to human mRNA for apolipoprotein B-100. Hybridization of mipomersen to the apoB mRNA results in degradation and loss of translation of the apoB protein
    • FDA-approved for Hx familial hyperlipidemia
    • Adverse effects include hepatic dysfunction and steatosis/hepatotoxicity, flu-like symptoms, nausea, and HA
  • Lopitamide - Microsomal triglyceride transfer protein inhibitor, resides in ER, prevents assembly of apoB-containing lipoproteins in enterocytes and hepatocytes
    • Inhibits synthesis of chylomicrons and VLDL in liver
    • Up to 50% reduction in plasma LDL levels
    • Major adverse effect is hepatic steatosis

Pharm-Spring (7 decks)

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