Pharmacology Test 2: Hypercholesteremia And Dyslipidemia Therapy

Front 1

Chylomicrons

Back 1

largest lipoproteins and have the lowest density

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VLDL

Back 2

endogenous triglycerides (are bad); catabolized by LPL, and have a short half-life

Front 3

IDL

Back 3

cholesteryl esters, converted to LDL by hepatic lipase

Front 4

LDL

Back 4

apoB-mediated uptake by LDL receptor, and have a long half-life

**Bad Cholesterol**

** > 190 is high **

Front 5

HDL

Back 5

phospholipids cholesteryl esters, removed by hepatic scavenger receptor B secreted to bile, steroid synthesis, VLDL synthesis

**Good Cholesterol**

** < 40 is low **

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Hypertriglyceridemia (VLDL)

Back 6

Diabetes, oral contraceptives (estrogen- which act to decrease LDL levels in the plasma), hypothyroidism, hypopituitarism, high sugar diet, and high alcohol intake (increased production and decreased clearance of VLDL)

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Hypercholesterolemia (LDL)

Back 7

High cholesterol (fat) diet, hypopituitarism, and hypothyroidism (decreased LDL receptors)

Front 8

Classification of Lipoprotein Analysis Results (mg/dl)

Back 8

Total Cholesterol: >240 is high

LDL Cholesterol ("bad"): >190 is high

HDL Cholesterol ("good"): <40 is low

Triglycerides: >500 is high

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Statins: Mechanism of Action

Back 9

Competition with HMG-CoA to prevent mevalonate synthesis, resulting in decrease of cholesterol synthesis and upregulation of LDL receptors

Front 10

Common Statins

Back 10

Lovastatin (Mevacor)

Simvastatin (Zocor)

Pravastatin (Pravachol)

Atorvastatin (Lipitor)

Rosuvastatin (Crestor)

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Long-Lasting Statins

Back 11

Atorvastatin and Rosuvastatin

Given as a single daily dose

Front 12

Short-Lived Statins

Back 12

Lovastatin, Simvastatin, Pravastatin

Given in multiple doses daily

Front 13

Statins: Side Effects

Back 13

Myopathies- major side effect; characterized by intense myalgia which progresses with the use of statin

Hepatotoxicity (take extra care of pts. with heavy drinking history)

Pregnancy

Children

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What Statins can be administered to children 11 and older?

Back 14

Atorvastatin, Lovastatin, and Simvastatin

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What Statins can be administered to children 8 or older?

Back 15

Provastatin

Front 16

Niacin (Nicotinic Acid)

Back 16

- Water soluble B vitamin complex
- The lipid lowering effect requires higher concentration than the vitamin effect
- Best agent available to increase HDL levels (30-40%)
- Decrease triglyceride levels (35-45%)
- Reduce the LDL levels (20-30%)
-Prescribed to a pt. with low HDL levels

Front 17

Niacin (Nicotinic Acid): Mechanism of Action

Back 17

Reduces triglyceride levels in the liver by inhibiting synthesis and esterification of free fatty acids; reduction in the free fatty acid levels leads to decrease in VLDL production and LDL levels

Front 18

Crystalline Niacin: Administration

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Immediate release

Available OTC

Best tolerated when starting with low doses (100mg twice daily) and increasing stepwise to 1.5-2g/daily

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Sustained Release Niacin: Adminstration

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Allows continuous release of the drug for 6-8 hours after ingestion (it is claimed to have less side effects)

Front 20

Extended-Release Niacin: Administration

Back 20

Requires a prescription and is less hepatotoxic

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Niacin Absorption

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Peak plasma concentration occurs 30-60 minutes after administration for the regular niacin

Sustained-release niacin was developed to lessen the side effects

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Niacin: Side Effects

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Digestive Tract: dyspesia (heart burn)--which is accentuated by coffee, tea, or alcohol; Should be avoided in pts. with a peptic ulcer

Cutaneous Effects: flushing and pruritus (itchy skin)--can be prevented by aspirin

Pregnancy: birth defects

Hepatotoxicity: elevated transaminases; has toxic effects to the liver

Hyperglycemia: limits niacin use in diabetic pts.; elevates uric acid levels and may reactivate gout

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Bile-acid Sequestrants (Resins): Mechanism of Action

Back 23

The oldest and safest lipid lowering agents.

Mech. of Action: Enhance bile acid synthesis; deplete hepatic cholesterol content; upregulate LDL receptors, but increase triglyceride synthesis

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Bile-acid Sequestrants (Resins): Side Effects and Administration

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Side Effects: bind directly and may interfere with absorption of many drugs, including statins

Administration:
- recommend administration of other drugs 1 hr. before or 3-4 hrs. after Resin dose
- recommended for pts. 11-20 yo and taken before eating
- administered as bulk (4-5g/dose)

Front 25

Fibric Acid Derivatives

Back 25

Mechanism of Action: bind to peroxisome proliferator activated receptors (PPAR) and stimulate beta-oxidation of fatty acids (prevents FA from being incorporated in VLDL and LDL levels); strongest agent to decrease triglyceride levels

Administration:
- Clofibrate: 2g/day
- Gemofibrozil: 600mg/twice daily
- Fenofibrate: 145 or 200 mg/day

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Fibric Acid Derivative Recommendations

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Pts. with type III hyperlipoproteinemia, severe hypertriglyceridemia (>1000mg/day), type II diabetes or metabolic syndrome
* Should not be used by children or pregnant women

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Fibric Acid Derivatives: Beneficial Effects

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Lipid lowering activity

Antithrombotic

Immunomodulation

Antiinflammatory Actions

Front 28

Ezetimibe: Inhibition of Dietary Cholesterol Uptake: Mechanism of Action

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Specifically blocks the function of Niemann-Pick C1-like 1 (NPC1L1) protein, a newly identified sterol influx transporter, facilitating cholesterol absorption

The compensatory increase in endogenous cholesterol synthesis is prevented by use of statins

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Ezetimibe: Inhibition of Dietary Cholesterol Uptake: Side Effects

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Increase in cancer incidence in pts. treated with Vytorin

Fetal abnormalities, so DO NOT give to pregnant women

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Ezetimibe: Inhibition of Dietary Cholesterol Uptake: Administration

Back 30

20 mg/daily- reduce LDL levels by 15-20%; recommended as a combinatorial therapy with Statins (Vytorin--no side effects)

Bile-acid sequestrants inhibit Ezetimibe absorption and should not be combined

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Combination Therapy: Statins + Niacin

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Enhances effects of statins but also increases risk of myopathies

**Good Combo.**

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Combination Therapy: Statins + Bile-acid Sequestrants

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Enhances effects of statins on LDL-C levels by 20-30%

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Triple Combinatory Therapy: Statins, Resins, Niacin

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Reduce LDL-C up to 70%

**Most Effective Combo.**

- but side effects are unbearable

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Vytorin: Combination of Simvastatin and Ezetimibe

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Decrease LDL-C levels by 60% after 24 weeks

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Summary of the Lipid Lowering Agents

Back 35

Statins: Big Decrease in LDL, Increase HDL, Decrease Triglyceride; liver toxicity, myopathies, pregnancy

Niacin (Nicotinic Acid): Decrease LDL, Increase HDL, Decrease TG; rash, ulcer, gout, diabetes, liver toxicity

Bile-acid Sequestrants (Resins): Decrease LDL, Increase HDL; constipation, GI discomfort

Fibric Acid Derivatives: Decrease LDL, Increase HDL, Big Decrease in TG; nausea, headache

Inhibitors of Cholesterol Absorption (Ezetimibe): Decrease LDL, Decrease HDL; pregnancy, resins inhibits absorption, may be not as safe as previously considered