Pharmacology Of Antihyperlipidemics

Question 1

Treatment of Dyslipidemia (5)

Answer 1

1. Lifestyle changes: should always be included in any treatment plan for reducing blood lipid levels. Many patients can control dyslipidemia entirely through non-pharmacologic means.
2. Monitor blood-lipid levels
3. Maintain weight; exercise
4. Reduce dietary saturated fats and cholesterol
5. Increase soluble fiber in diet

Question 2

Drug Classes for Antihyperlipidemic Therapy (7)

Answer 2

1. Inhibitors of HMG-CoA Reductase
2. PCSK9 Inhibitors
3. Blie Acid Sequestrants
4. Niacin
5. Fibric Acid Agents
6. Ezetimibe
7. Omega-3 Fatty Acids

Question 3

Inhibitors of HMG-CoA Reductase (Statins) [General and MOA]

Answer 3

General: Interfere with the synthesis of cholesterol. First drugs of choice. Numerous clinical studies have documented their safety and efficacy in reducing morbidity and mortality associated with CAD and stroke. Includes fluvastatin, lovastatin, rosuvastatin, simvastatin, and atorvastatin.

MOA: Act by inhibiting HMG-CoA reductase, a key liver enzyme involved in the synthesis of cholesterol. Also enhances the uptake of LDL by the liver by up-regulating the expression of LDL receptors via increases in SREBP activity. Used to reduce serum LDL levels.

Question 4

Inhibitors of HMG-CoA Reductase (Statins) [Considerations, ADRs, and PK]

Answer 4

Considerations: Not all statins have the same efficacy. Newer statins are better absorbed, have longer half lives and higher affinity for the reductase enzyme (rosuvastatin and atorvastatin).

ADRs:

1. Mild, transient GI symptoms
2. Rash, headache
3. Elevation in liver enzymes or liver damage
4. Myopathy (muscle pain) possibly leading to rhabdomyolysis

PK: Extensive first-pass metabolism, 5-20% of dose reaches general circulation.
CYP450, 3A4 metabolism - lovastatin, simvastatin, atorvastatin.
CYP450, 2C9 metabolism - fluvastatin.
Lovastatin and simvastatin are “prodrugs” as they are activated in the GI tract.

Question 5

Inhibitors of HMG-CoA Reductase (Statins) [Parameters and Contraindications]

Answer 5

Parameters: Monitor liver function tests. Watch for signs of GI upset. Administer shorter half-life statins like lovastatin at night since HMG CoA-reductase activity is greatest during nighttime due to sleep/resting.

Contraindications: Do not use with pregnancy or breast feeding. Category X.

Question 6

Lovastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)

Answer 6

Bioavailability: less than 5%
Prodrug: yes
Metabolism: CYP3A4
Half-life: 1-2 hours
Dosing: PM

Question 7

Pravastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)

Answer 7

Bioavailability: 17%
Prodrug: no
Metabolism: Non-CYP3A4
Half-life: 77 hours
Dosing: anytime

Question 8

Simvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)

Answer 8

Bioavailability: less than 5%
Prodrug: yes
Metabolism: CYP3A4
Half-life: 3 hours
Dosing: PM

Question 9

Fluvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)

Answer 9

Bioavailability: 24%
Prodrug: no
Metabolism: CYP2C9
Half-life: 3 hours
Dosing: PM

Question 10

Atorvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)

Answer 10

Bioavailability: 14%
Prodrug: yes
Metabolism: CYP3A4
Half-life: 14 hours, 20-30 hours
Dosing: anytime

Question 11

Rosuvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)

Answer 11

Bioavailability: 20%
Prodrug: no
Metabolism: minimal
Half-life: 19 hours
Dosing: anytime

Question 12

Pitavastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)

Answer 12

Bioavailability: 51%
Prodrug: no
Metabolism: minimal
Half-life: 12 hours
Dosing: anytime

Question 13

HMG-CoA Reductase Inhibitors [Statins] (Clinical effects)

Answer 13

Decreased LDL by 22-55% (decreases endogenous cholesterol synthesis, increases uptake of plasma LDL by stimulating transcription of the LDL receptor gene).
Decreases triglycerides by 10-30% (decreases VLDL production).
Increases HDL by 5-15% (increases apo A-1 synthesis).

Question 14

PCSK9 Inhibitors (General and MOA)

Answer 14

General: Some patients with familial hypercholesterolemia have a mutation in the PCSK9 gene (chromosome 1). This mutation produces excess levels of a protein that promotes degradation of LDL receptors on the surface of hepatocytes.

MOA: Blocking PCSK9 can prevent LDL receptors from being broken down and thus more LDL cholesterol would be taken up by the liver.

Question 15

PCSK9 Inhibitors Alirocumab (Praulent) and Evolocumab (Repatha)

Answer 15

MOA: Monoclonal antibodies that inactivate protein PCSK9.

Clinical efficacy: 39-62% reduction in LDL cholesterol.

Question 16

PCSK9 Inhibitors Alirocumab (Praulent) and Evolocumab (Repatha)

Answer 16

PK: By injection only once every 2 weeks.

ADRs:

1. Nasopharyngitis (11%)
2. Injection site reactions (7%)
3. Influenza (5.7%)

Question 17

Bile-Acid Sequestrants [BAS] (General and MOA)

Answer 17

General: Ion-exchange resins.

MOA: Binds bile salts in the intestine to prevent their recycling by the liver. Bile salts help with the break down of fat in the intestines for easier absorption into circulation. Lowers cholesterol levels.

Question 18

Bile-Acid Sequestrants [BAS (Cholestyramine, Colestipol, Colesevalam)] (PK, Clinical Efficacy, and Advantages)

Answer 18

PK: Taken PO. Used sprinkled on food or taken as a slurry before a meal. Also available in pill form.

Clinical Efficacy: 8-24% reductions in LDL levels. 3-5% increase in HDL. Synergistic effects with statins are possible.

Advantages: Non-systemic. Acts only in GI tract.

Question 19

Bile-Acid Sequestrants [BAS (Cholestyramine, Colestipol, Colesevalam)] (ADRs and Parameters)

Answer 19

ADRs:

1. GI bloating, constipation, irritation
2. May raise serum triglyceride levels
3. May bind other drugs in the intestine (thiazides, furosemide, digoxin, coumarin, levothyroxine) - Avoid taking these at the same time.

Parameters: Monitor for significant GI effects. Obtain careful history for past GI disorders. Caution with other oral medications.

Question 20

Niacin [Nicotinic acid (Nispan)] (General, MOA, and Clinical Efficacy)

Answer 20

General: Vitamin B3. Primary use is to reduce VLDL triglycerides and increase HDL levels.

MOA: Alters the activity of lipase enzymes that metabolize triglycerides and lipids. Decreases hormone-sensitive lipase activity, decreases plasma free fatty acids, decreases synthesis of triglycerides, decreases plasma VLDL and LDL, decreases cholesterol delivery to peripheral cells. Decreases apo A-1 clearance, increases plasma HDL, increases cholesterol delivery to the liver, and increases cholesterol excretion in bile.

Clinical Efficacy: TAG decrease up to 45%. LDL decrease up to 20%. HDL increase up to 30%.

Question 21

Niacin [Nicotinic acid (Nispan)] (PK and ADRs)

Answer 21

PK: Requires very high doses (1-4 g/day) for therapeutic effect. Not used alone, but can be used with statins. Caution- available over the counter.

ADRs:

1. Flushing (blocked by aspirin)
2. Pruritus
3. GI distress
4. Rhabdomyolysis
5. Hepatotoxicity
6. Worsens gout
7. Impaired glucose control (avoid in diabetics)

Question 22

Niacin [Nicotinic acid (Nispan)] (Parameters)

Answer 22

Parameters: Monitor liver function, uric acid levels (if predisposed to gout), blood glucose levels (if diabetic). Avoid in patients with peptic ulcer disease (PUD).

Question 23

Fibric Acid Derivatives [Fibrates (Gemfibrozil and Fenofibrate)] (MOA and Clinical Efficacy)

Answer 23

MOA: Believed to work by activating a lipase (PPAR-alpha — peroxisome proliferator-activated receptor alpha), which breaks down cholesterol. Also suppresses the release of free fatty acid from adipose tissue; inhibits synthesis of triglycerides in the liver.

Clinical Efficacy: Mainly used to treat high levels of triglycerides. Only modest effects on LDL. Less effective than statins.

Question 24

Fibric Acid Derivatives [Fibrates (Gemfibrozil and Fenofibrate)] (Considerations, ADRs, and Parameters)

Answer 24

Considerations: Potentiate the effects of oral anticoagulants. When used with statins, increased risk of myositis, myalgias, and rhabdomyolysis. Labs may show decreased hemoglobin, hematocrit, and WBC. Also may show increased activated clotting time, LDH, and bilirubin.

ADRs:

1. Abdominal discomfort, diarrhea, nausea
2. Blurred vision, headache
3. Increased risk of gallstones (older drug: Clofibrate)
4. Prolonged prothrombin time
5. Liver studies may show increased enzyme levels

Parameters: Assess for complaints of GI distress before starting. Use with warfarin may potentiate anticoagulant effects. Monitor PT/INR.

Question 25

Ezetimibe [Zetia] (General, MOA, Clinical Efficacy, and ADRs)

Answer 25

General: Often combined with a statin drug (Vytorin). Currently recommended only when patients have not responded to other therapy. Expensive.

MOA: Inhibits the absorption of cholesterol from the gut by blocking cholesterol receptors (NPC1L1).

Clinical Efficacy: Reduces total cholesterol, LDL, and triglyceride levels (10-15% alone). Minimally increases HDL levels alone.

ADRs: Serious side effects uncommon.

Question 26

Omega-3 Fatty Acids [Omacor] (General, MOA, PK, and Clinical Efficacy)

Answer 26

General: Fish oils— eicospenatenoic acid (EPA) and docosahexaenoic acid (DHA). Omacor is enriched (84% EPA and DHA). Added to drug therapy to lower plasma triglycerides.

MOA: Reduces triglyceride biosynthesis through PPAR-alpha activation (similar to fibrates).

PK: 4 g/day.

Clinical Efficacy: May reduce triglycerides up to 50%.