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Chapter: Basic & Clinical Pharmacology : Agents Used in Dyslipidemia

NIACIN (Nicotinic Acid)

Niacin (but not niacinamide) decreases VLDL and LDL levels, and Lp(a) in most patients. It often increases HDL levels signifi-cantly.


Niacin (but not niacinamide) decreases VLDL and LDL levels, and Lp(a) in most patients. It often increases HDL levels signifi-cantly.

Chemistry & Pharmacokinetics

Niacin (vitamin B3) is converted in the body to the amide, which is incorporated into niacinamide adenine dinucleotide (NAD). It is excreted in the urine unmodified and as several metabolites.

Mechanism of Action

Niacin inhibits VLDL secretion, in turn decreasing production of LDL (Figure 35–2). Increased clearance of VLDL via the LPL pathway contributes to reduction of triglycerides. Niacin has no effect on bile acid production. Excretion of neutral sterols in the stool is increased acutely as cholesterol is mobilized from tissue pools and a new steady state is reached. The catabolic rate for HDL is decreased. Fibrinogen levels are reduced, and levels of tissue plasminogen activator appear to increase. Niacin inhibits the intracellular lipase of adipose tissue via receptor-mediated signaling, possibly reducing VLDL production by decreasing the flux of free fatty acids to the liver. Sustained inhibition of lipolysis has not been established, however.

Therapeutic Uses & Dosage

In combination with a resin or reductase inhibitor, niacin normal-izes LDL in most patients with heterozygous familial hypercholes-terolemia and other forms of hypercholesterolemia. These combinations are also indicated in some cases of nephrosis. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. It is useful in patients with combined hyperlipidemia and in those with dysbetalipopro-teinemia. It is clearly the most effective agent for increasing HDL and the only agent that may reduce Lp(a).

For treatment of heterozygous familial hypercholesterolemia, most patients require 2–6 g of niacin daily; more than this should not be given. For other types of hypercholesterolemia and for hypertriglyceridemia, 1.5–3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually.


Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each dose when niacin is started or the dose increased. Taking 81–325 mg of aspirin one half hour before-hand blunts this prostaglandin-mediated effect. Ibuprofen, once daily, also mitigates the flush. Tachyphylaxis to flushing usually occurs within a few days at doses above 1.5–3 g daily. Patients should be warned to expect the flush and understand that it is a harmless side effect. Pruritus, rashes, dry skin or mucous mem-branes, and acanthosis nigricans have been reported. The latter contraindicates use of niacin because of its association with insulin resistance. Some patients experience nausea and abdominal dis-comfort. Many can continue the drug at reduced dosage, with inhibitors of gastric acid secretion or with antacids not containing aluminum. Niacin should be avoided in most patients with severe peptic disease.

Reversible elevations in aminotransferases up to twice normal may occur, usually not associated with liver toxicity. However, liver function should be monitored at baseline and at appropriate intervals. Rarely, true hepatotoxicity may occur, and in these cases the drug should be discontinued. The association of severe hepatic dysfunction, including acute necrosis, with the use of over-the-counter sustained-release preparations of niacin has been reported. This effect has not been noted to date with an extended-release preparation, Niaspan, given at bedtime in doses of 2 g or less. Carbohydrate tolerance may be moderately impaired, especially in obese patients, but this is usually reversible except in some patients with latent diabetes. Niacin may be given to diabetics who are receiving insulin and to some receiving oral agents. Niacin may increase insulin resistance in some patients. This can often be addressed by increasing the dose of insulin or the oral agents. Hyperuricemia occurs in some patients and occasionally precipi-tates gout. Allopurinol can be given with niacin if needed. Red cell macrocytosis is frequently observed with higher doses of niacin and is not an indication for discontinuing treatment. Significant platelet deficiency can occur rarely and is reversible on cessation of treatment. Rarely, niacin is associated with arrhythmias, mostly atrial, and with macular edema. Patients should be instructed to report blurring of distance vision. Niacin may potentiate the action of antihypertensive agents, requiring adjustment of their dosages. Birth defects have been reported in animals given very high doses.

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