Medical Pharmacology Chapter 11:  Drugs Used in Treating Hyperlipidemia

• Lipoprotein Disorders

  • Overview: lipoprotein disorders

    • Evaluation: Serum lipid measurement following 10-hour fast

    •  CHD risk:

      • Directly proportional to atherogenic lipoproteins concentration

      • Indirectly proportional to HDL levels

      • Triglyceride levels, preferably less than 150 mg/dL

  • Primary Hypertriglyceridemia

    • Definition: triglyceride plasma concentration > 90th or 95th percentile for age and gender (as determined following an overnight fast)

    • Isolated plasma triglycerides elevation may be due to increased VLDL or combinations of elevated VLDL and chylomicrons (rarely a result of elevated chylomicrons only)

      •  Eruptive xanthomas may occur in isolated hypertriglyceridemia

        •  Small, orange-red papules (trunk/extremities; triglyceride levels > 1000 mg/dL  chylomicronemia)

          • Eruptive Xanthomas

            Samsuddin "Eruptive xanthomas" http://www.doctorshangout.com/photo/eruptive-xanthomas

      •  At 1000 mg/dL:

        •  Orange-yellow retinal vessels (lipemia retinalis)

        •  Major risk at this plasma triglyceride concentration: pancreatitis

    • Typical plasma triglycerides elevation: caused by increased hepatic VLDL triglyceride synthesis and secretion

      • Regulation of hepatic triglyceride synthesis:

        •   Free fatty acid availability

        •   Hepatic glycogen levels

        •   Balance between insulin and glucagon

      • Conditions associated with hypertriglyceridemia:

        •   Obesity, insulin resistance, alcohol consumption, inactivity, excessive intake of simple sugars and saturated fats.

        •   At VLDL triglyceride levels > 1000 mg/dL, lipoprotein lipases may become saturated.

  • Familial Hypertriglyceridemia: (severe)

    • Autosomal dominant (For mixed lipemia-- various modes of inheritance)

    • Possible mechanisms: VLDL over production and reduced triglyceride-rich lipoprotein catabolism

    • Fasting triglyceride range: 200-750 mg/dL, with increased VLDL triglycerides only

    • Factors that increase VLDL production worsens lipemia (VLDL and chylomicrons -- competing lipoprotein lipase substrates)

    • Most patients: obese

    • Clinical complaints (depending on lipemia severity): eruptive xanthomas, epigastric pain, lipemia retinalis, pancreatitis

    • Treatment: dietary:   alcohol avoidance, reduced fat intake, avoid exogenous estrogen, weight reduction; some patients may require gemfibrozil (Lopid) or niacin (vitamin B3)

  • Familial Hypertriglyceridemia: (moderate, endogenous lipemia)

    • Multiple genetic factors

    • Made worse by factors that increased hepatic VLDL secretion (hypertrophic obesity, alcohol, exogenous estrogen intake, diabetes)

    • Treatment: -- indication presence of atherosclerosis (in the patient or in the patient's family)

      • Weight reduction

      • Dietary fat restriction

      • Alcohol avoidance

      • If necessary, gemfibrozil (Lopid) or niacin (vitamin B3)

  • Familial Combined Hyperlipoproteinemia

    • Elevated VLDL and/or LDL

    • Mechanism: 200% increase in hepatic VLDL secretion

    • Increased CHD risk: Drug therapy (niacin or a resin in combination with niacin)

  • Familial Lipoprotein Lipase Deficiency

    • Autosomal recessive (absence/impairment of lipoprotein lipase/lipoprotein lipase cofactor)

    • Dramatic chylomicron accumulation in plasma:

    • Lipemia worsened by estrogens and pregnancy

    • Clinical presentations (beginning in infancy) include:

      •  Pancreatitis

      •  Eruptive xanthomas

      •  Hepatomegaly

      •  Splenomegaly

      •  Bone marrow foam cell infiltration

      •  At triglyceride levels > 1000 mg/dL --lipemia retinalis

        • Lipemia Retinalis

          Attribution Harper CL Lipemia Retinalis (last modified Bozell C) October 28, 2019 and November 1, 2019 "Fundus photo of a 2-month-old female diagnosed with lipemia retinalis." Retinal Image Bank:  https://imagebank.asrs.org/file/39320/lipemia-retinalis

       

  • Familial Apoprotein CII Deficiency

    • Rare autosomal recessive

    • Presentations similar to familial lipoprotein lipase deficiency

  • Familial Dysbetalipoproteinemia

    • Accumulation of chylomicrons and VLDL reminants

    • Low LDL; high serum cholesterol and triglycerides

    • Clinical Presentations:  Familial Dysbetalipoproteinemia:

      • Tuberous/tuberoeruptive xanthomas

      • Planar xanthomas:palmar creases

      • Common: obesity and impaired glucose tolerance-- worsening lipemia

      • Peripheral/coronary atherosclerosis

    • Treatment:  Familial Dysbetalipoproteinemia:

      • Weight reduction

      • Reduced fat, cholesterol, alcohol intake

      • Niacin (vitamin B3) or gemfibrozil (Lopid) may be needed (typically at low doses).

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.

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.

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