Pharmacology Of Antihyperlipidemics Flashcards
Treatment of Dyslipidemia (5)
- 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.
- Monitor blood-lipid levels
- Maintain weight; exercise
- Reduce dietary saturated fats and cholesterol
- Increase soluble fiber in diet
Drug Classes for Antihyperlipidemic Therapy (7)
- Inhibitors of HMG-CoA Reductase
- PCSK9 Inhibitors
- Blie Acid Sequestrants
- Niacin
- Fibric Acid Agents
- Ezetimibe
- Omega-3 Fatty Acids
Inhibitors of HMG-CoA Reductase (Statins) [General and MOA]
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.
Inhibitors of HMG-CoA Reductase (Statins) [Considerations, ADRs, and PK]
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:
- Mild, transient GI symptoms
- Rash, headache
- Elevation in liver enzymes or liver damage
- 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.
Inhibitors of HMG-CoA Reductase (Statins) [Parameters and Contraindications]
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.
Lovastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)
Bioavailability: less than 5% Prodrug: yes Metabolism: CYP3A4 Half-life: 1-2 hours Dosing: PM
Pravastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)
Bioavailability: 17% Prodrug: no Metabolism: Non-CYP3A4 Half-life: 77 hours Dosing: anytime
Simvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)
Bioavailability: less than 5% Prodrug: yes Metabolism: CYP3A4 Half-life: 3 hours Dosing: PM
Fluvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)
Bioavailability: 24% Prodrug: no Metabolism: CYP2C9 Half-life: 3 hours Dosing: PM
Atorvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)
Bioavailability: 14% Prodrug: yes Metabolism: CYP3A4 Half-life: 14 hours, 20-30 hours Dosing: anytime
Rosuvastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)
Bioavailability: 20% Prodrug: no Metabolism: minimal Half-life: 19 hours Dosing: anytime
Pitavastatin (Bioavailability, prodrug?, metabolism, half-life, and dosing)
Bioavailability: 51% Prodrug: no Metabolism: minimal Half-life: 12 hours Dosing: anytime
HMG-CoA Reductase Inhibitors [Statins] (Clinical effects)
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).
PCSK9 Inhibitors (General and MOA)
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.
PCSK9 Inhibitors Alirocumab (Praulent) and Evolocumab (Repatha)
MOA: Monoclonal antibodies that inactivate protein PCSK9.
Clinical efficacy: 39-62% reduction in LDL cholesterol.
PCSK9 Inhibitors Alirocumab (Praulent) and Evolocumab (Repatha)
PK: By injection only once every 2 weeks.
ADRs:
- Nasopharyngitis (11%)
- Injection site reactions (7%)
- Influenza (5.7%)
Bile-Acid Sequestrants [BAS] (General and MOA)
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.
Bile-Acid Sequestrants [BAS (Cholestyramine, Colestipol, Colesevalam)] (PK, Clinical Efficacy, and Advantages)
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.
Bile-Acid Sequestrants [BAS (Cholestyramine, Colestipol, Colesevalam)] (ADRs and Parameters)
ADRs:
- GI bloating, constipation, irritation
- May raise serum triglyceride levels
- 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.
Niacin [Nicotinic acid (Nispan)] (General, MOA, and Clinical Efficacy)
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%.
Niacin [Nicotinic acid (Nispan)] (PK and ADRs)
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:
- Flushing (blocked by aspirin)
- Pruritus
- GI distress
- Rhabdomyolysis
- Hepatotoxicity
- Worsens gout
- Impaired glucose control (avoid in diabetics)
Niacin [Nicotinic acid (Nispan)] (Parameters)
Parameters: Monitor liver function, uric acid levels (if predisposed to gout), blood glucose levels (if diabetic). Avoid in patients with peptic ulcer disease (PUD).
Fibric Acid Derivatives [Fibrates (Gemfibrozil and Fenofibrate)] (MOA and Clinical Efficacy)
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.
Fibric Acid Derivatives [Fibrates (Gemfibrozil and Fenofibrate)] (Considerations, ADRs, and Parameters)
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:
- Abdominal discomfort, diarrhea, nausea
- Blurred vision, headache
- Increased risk of gallstones (older drug: Clofibrate)
- Prolonged prothrombin time
- 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.
