Mechanism of Action

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Nicotinic acid decreases formation and secretion of VLDL by the liver (mechanism III in Fig. 23.2). This action appears secondary to its ability to inhibit fatty acid mobilization from adipose tissue. Circulating free fatty acids provide the main source of fatty acids for hepatic triglyceride synthesis, and lowering triglyceride synthesis lowers VLDL formation and secretion by the liver. Since plasma VLDL is the source of LDL, lowering VLDL can ultimately lower LDL. In addition, nicotinic acid shifts LDL particles to larger (more buoyant) sizes. The larger LDL particles are thought to be less atherogenic. Nicotinic acid can also significantly increase plasma HDL levels; the mechanism is unknown.

Clinical Uses

Used alone, nicotinic acid can decrease plasma LDL cholesterol levels by 15 to 30%. It can also be used in combination therapy with the statins or the bile acid-sequestering resins to augment reduction of very high LDL levels. Because nicotinic acid can lower plasma triglycerides by 40% or more, it is useful in treating familial hypertriglyceridemia type IV (Table 23.3), and in combination with the statins it is useful in treating combined hyperlipidemia type lib. As described later with the fibrates, patients with high plasma triglycerides plus low HDL are at increased risk for CHD. Nicotinic acid is useful for treating these patients, since it can both lower triglycerides and raise HDL.

Adverse Effects

Compliance with nicotinic acid therapy can be poor because the drug can produce an intense cutaneous flush. This can be reduced by beginning the drug in stepped doses of 250 mg twice daily and increasing the dose monthly by 500 to 1000 mg per day to a maximum of 3000 mg per day. Taking nicotinic acid on a full stomach (end of meal) and taking aspirin before dosage can reduce the severity of flushing. Time-release forms of nicotinic acid may also decrease cutaneous flushing. Nicotinic acid can cause gastrointestinal (GI) distress, liver dysfunction (especially at high doses), decreased glucose tolerance, hyperglycemia, and hyperuricemia. Thus, it is contraindicated in patients with hepatic dysfunction, peptic ulcer, hyperuricemia, or diabetes melli-tus. A paradox associated with nicotinic acid is that it is the most widely available hypolipidemic drug (it is sold over the counter), yet its use requires the closest management by the physician.

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