dilatation of skin arterioles, causing reddish skin color – usually lasts for about 15 to 30 minutes, although sometimes can persist for weeks. Typically, the face is affected, but the reaction can extend to neck and upper chest. The cause is blood vessel dilation due to elevation in prostaglandin GD2 (PGD2) and serotonin. Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction. Flushing is sometimes accompanied by a prickly or itching sensation, in particular, in areas covered by clothing. Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway. Aspirin taken half an hour before the niacin prevents flushing, as does ibuprofen. Taking niacin with meals also helps reduce this side effect. Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most people no longer experience flushing. Slow- or "sustained"-release forms of niacin have been developed to lessen these side effects. Liver damage Niacin in medicinal doses can cause modest elevations in serum transaminase and unconjugated bilirubin, both biomarkers of liver injury. The increases usually resolve even when drug intake is continued. However, less commonly, the sustained release form of the drug can lead to serious hepatotoxicity, with onset in days to weeks. Early symptoms of serious liver damage include nausea, vomiting and abdominal pain, followed by jaundice and pruritus. The mechanism is thought to be a direct toxicity of elevated serum niacin. Lowering dose or switching to the immediate release form can resolve symptoms. In rare instances the injury is severe, and progresses to liver failure. Diabetes The high doses of niacin used to treat hyperlipidemia have been shown to elevate fasting blood glucose in people with type 2 diabetes. Long-term niacin therapy was also associated with an increase in the risk of new-onset type 2 diabetes. Other adverse effects High doses of niacin can also cause niacin maculopathy, a thickening of the macula and retina, which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases. Niaspan, the slow-release product, has been associated with a reduction in platelet content and a modest increase in prothrombin time. Pharmacology Pharmacodynamics Activating HCA2 has effects other than lowering serum cholesterol and triglyceride concentrations: antioxidative, anti-inflammatory, antithrombotic, improved endothelial function and plaque stability, all of which counter development and progression of atherosclerosis. Niacin inhibits cytochrome P450 enzymes CYP2E1, CYP2D6 and CYP3A4. Niacin produces