• Dietary Management

  • Preferred initial approach except for conditions in which drug and diet management should begin simultaneously:

    •   Familial hypercholesterolemia

    •   Familial combined hyperlipidemia

  • Major dietary factors influencing plasma LDL levels:

    •  Cholesterol intake

    •  Saturated fat intake

  • Major dietary factor influencing plasma triglycerides (hypertriglyceridemia)

    • Total fat intake

  • Cholesterol and saturated fats increase ­ LDL concentration independently

  • For patients with elevated LDL:

    •   Total fat calories: 20-25% (saturated fats < 8% of total calories); monounsaturated fats predominate within fat allowance

    •   Cholesterol < 200 mg/dL

    •   Expectable serum cholesterol reduction (with this diet): 10%-20%

    •   Weight reduction

    •   Caloric restriction (especially for patients with increased VLDL and IDL)

  • For patients with elevated triglycerides:

    • Omega-3 fatty acids (fish oils): significant serum triglyceride level reduction ¯ in some patients

    • Omega-6 fatty acids (vegetable oils): may increase­ triglyceride levels in these patients

Pharmacological Management of Hyperlipidemia

• "Cholesterol (Antilipemic) Medications-Pharmacology-Cardiovascular"

  Attribution: Parker C BSN, RN CWCN, PHN Cholesterol (Antilipemic) Medications-Cardiovascular | https://www.youtube.com/watch?v=wSclSoHOHk0 (November 4, 2020) Level UP RN https://www.youtube.com/channel/UCSlJ8BB17Ex9s4mrg7DEYCw

• Overview:  Drug Management

  •  Diet: adjunct to drug treatment

  •  Avoid drug therapy in women likely to become pregnant or if lactating

  •  Bile acid resins treatment for childrent (> 7 years old) with heterozygous familial hypercholesterolemia

• Niacin (nicotinic acid)

  • Overview: niacin

    • Decreases VLDL and LDL plasma levels

  • Chemistry and pharmacokinetics:niacin

    •   Water-soluble vitamin

    •   Urinary excretion:

  • Some Mechanisms of Action:niacin

    • Probable: VLDL secretion inhibition which decreases LDL production

    • Pncreased VLDL clearance

    • Decreased cholesterol synthesis

    • Decreased HDL catabolism (increasing HDL cholesterol plasma levels)

  • Clinical Use:  niacin (vitamin B3)

    • Heterozygous familial hypercholesterolemia:

    • Severe mixed lipemia (inadequately responsive to diet)

    • Combined hyperlipoproteinemia

    • Familial dysbetalipoproteinemia

    • Hypercholesterolemia:

    • Most effective agent in increasing HDL cholesterol

  •  Toxicity: niacin (vitamin B3)

    • Treatment initiation or upon increasing dosage: cutaneous vasodilation; sensation of warmth.

      • Aspirin pre-treatment (30 minutes before dosing) reduces this effect {prostaglandin-mediated}

      • Ibuprofen (once daily) alleviates us affect also

    • Acanthosis appearance: contraindication for continued niacin treatment;  association with insulin resistance

    • In patients with severe peptic disease: avoid niacin

    • Hyperuricemia (frequency: 20%; gout may occur; allopurinol may be given with niacin to manage hyperuricemia)

    • Hypotension, especially in patients receiving antihypertensive medication

• Gemfibrozil (Lopid)

  • Gemfibrozil (Lopid)

  • Overview: gemfibrozil (Lopid)

    • Reduces VLDL plasma levels

    • Increases lipoprotein lipases activity

  • Pharmacokinetics:  gemfibrozil

    • Well absorbed (intestine)

    • Renal excretion: 70%; primarily unmodified

  • Mechanism of Action:  gemfibrozil (Lopid)

    • Probably increases lipoprotein triglyceride lipolysis through lipoprotein lipase action

  • Clinical Use:  gemfibrozil (Lopid)

    • Hypertriglyceridemia -- (VLDL predominates)

    • Dysbetalipoproteinemia

  • Toxicity:  gemfibrozil

    • Gastrointestinal upset, myopathy, arrhythmias, hypokalemia, aminotransferase elevation, alkaline phosphatase elevation, skin rashes

    • Avoid in patients with hepatic or renal dysfunction

    • Small increase in gallstone incidence

    • Gemfibrozil should not be used in patients with combined hyperlipidemia and symptoms of CHD

Bile Acid-Binding Resins

•  Overview: Bile Acid-Binding Resins

  • Colestipol (Colestid) and cholestyramine (Questran, Questran Light): clinical use --

    • Management of elevated LDL levels

    • Resin treatment in patients with hypertriglyceridemia + elevated LDL  VLDL levels may be further increased

  Chemistry and Pharmacokinetics: Bile acid-binding resins

  • Colestipol (Colestid) andcholestyramine (Questran, Questran Light):

    • Polymeric cationic exchange resins

    • Water insoluble

    • Prevent reabsorption to bile acids by binding to them in the intestine

    • Resin: not absorbed systemically

• Mechanism of Action: Bile acid-binding resins:

  • Bile acids (cholesterol metabolites): 95% reabsorbed in the jejunum and ileum

    • In the presence of binding resins: excretion ­increases up to 10X

    • Increased bile acid clearance causes increased conversion of cholesterol to bile acids (in the liver, 7-a hydroxylation)

• Clinical Uses: Bile acid-binding resins:

  • In patients with familial hypercholesterolemia:

    • 20% reduction in LDL cholesterol ( at maximal bile acid-binding resin dosages)

    • In less severe hypercholesterolemia: there is greater response at  lower dosages

    • In patients with combined hyperlipidemia (LDL elevation) bile acid-binding resins lead to increased VLDL {requiring use of second drug (e.g. niacin)}

•  Toxicity:Bile acid-binding resins:

  •  Most common:

    • Constipation

    • Bloating {managed by increasing dietary fiber or adding psyllium seed to the resin preparation}

  •  Drug-Drug Interactions:-- reduced absorption (neutral, cationic, anionic drugs)

Reductase Inhibitors (Competitive Inhibitors of HMG-CoA reductase)

• Overview: reductase inhibitors (Statins)

• "Statins Pharmacology Nursing NCLEX"

  Attribution: "Nurse Sarah, BSN, RN" Statin Pharmacology Nursing NCLEX HMG-CoA Reductase Inhibitors Antilipemic Cholesterol Lowering. https://www.youtube.com/watch?v=k76JLAFRsao (October 6, 2020) RegisteredNurseRN https://www.youtube.com/@RegisteredNurseRN

• Drugs: structural analogs HMG-CoA

  • Agents include:  lovastatin (Mevacor), atorvastatin (Lipitor), fluvastatin (Lescol), pravastatin (Pravachol), simvastatin (Zocor), rosuvastatin (Crestor).

Chemistry and Pharmacokinetics: reductase inhibitors

• Prodrugs: lovastatin (Mevacor)and simvastatin (Zocor)

• Active drugs: atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol).

• Variable levels of absorption

• All reductase inhibitors: high first pass effect

• Mechanism of Action:reductase inhibitors

  • HMG-CoA reductase:

    • Catalyzes first committed sterol biosynthesis step

  • Lovastatin (active form) and congeners: HMG-CoA structural analogs causes partial inhibition of HMG-CoA reductase

  • Reductase inhibitor leads to an  increase in LDL high-affinity receptors

    • Reduces plasma LDL

  • Primary hepatic site of action

  • Small decreases in plasma triglycerides; slight increase in HDL cholesterol

• Clinical Use: reductase inhibitors

  • Treatment of elevated LDL plasma levels:-- monotherapy or with bile acid-binding resins or niacin

  •   Contraindications:

    •  Women: do not use of pregnant, lactating or likely to become pregnant

    •  Children: only use in children with:

      • Heterozygous familial hypercholesterolemia

      • Homozygous familial hypercholesterolemia with some LDL receptor function

• Toxicity: reductase inhibitors

  • Some increase in creatinine kinase (frequency: 10%, intermittent)

    •  Reductase inhibitor-induced myopathy: more likely to the presence of other drugs such as:

      • Cyclosporine, fibric acid derivatives, azole antifungal drugs (particularly itraconazole (Sporanox)), macrolide antibiotics (e.g. erythromycin), danazol, and perhaps niacin (vitamin B3)

      • Frequent measures of creatinine kinase activity is recommended

Drug Combination Treatment

• Overview: drug combination treatment

  • Appropriate under some conditions

  • Gemfibrozil (Lopid) and Bile Acid-Binding Resin

    • May be useful: familial combined hyperlipidemia (patient niacin intolerant)

      • Possible increase cholelithiasis risk

  • Reductase inhibitor and Binding Acid-Binding Resin

    • HMG-CoA reductase inhibitors + bile acid-binding resins are highly synergistic effects

    • Useful: familial hypercholesterolemia

    • May not control elevated VLDL in patients with familial combined hyperlipidemia

• Niacin and Bile Acid-Binding Resin

• Niacin and Reductase Inhibitor:

• Combination of Resin, Niacin, and Reductase Inhibitor.

1. Primary Reference: Malloy, M. J, and Kane, J. P., Agents Used in Hyperlipidemia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 563-577.

2. Primary Reference: Ginsberg, H. N and Goldberg, I. J. Disorders of Intermediary Metabolism: Disorders of Lipoprotein Metabolism, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2138-2149.