Niacin (a combination of nicotinic acid and nicotinamide), a B vitamin (vitamin B3), is a pharmacotherapeutic agent that has been used since 1955, making it the oldest, pleiotropic hypolipidemic agent. The vitamin plays a role in both neuroprotection and neuronal death, giving it the utmost importance in the proper functioning of the central nervous system (CNS), neuronal development, and function.
Niacin has seen extensive use, alone or in combination, with statin medications (hydroxymethyl glutaryl coenzyme A reductase inhibitors) in the reduction of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL), and lipoprotein levels. Moreover, niacin is the most potent agent used to increase plasma high-density lipoprotein (HDL) cholesterol. In patients with diabetes mellitus or mixed dyslipidemia, niacin has demonstrated in clinical trials that it can counterbalance cardiovascular risk in this patient population, hence decreasing cardiovascular morbidity and mortality, especially when used in combination with statin drugs.
Niacin, after undergoing biochemical reactions in the mitochondria with nicotinamide, and tryptophan forms nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). NAD and NADP are the active forms of niacin which, when reduced to NAD(H) and NADP(H) respectively, participates in catabolic redox reactions and are cofactors in anabolic redox reactions.
Although niacin has been in use for many years, its beneficial pleiotropic effects make it a challenge to grasp its mechanism of action fully. However, a targeted mechanism of action based on certain effects niacin has in the human body are:
Niacin is available in two chemical forms. As nicotinic acid only, used for hyperlipoproteinemia or peripheral vascular disease. Another form is both nicotinic acid and nicotinamide (niacinamide), used for nutritional supplementation or pellagra. Oral extended-release tablets come in 250 mg, 500 mg, 750mg, 1000 mg, 3000 mg. Dosing of 1 to 3 grams/day was found to reduce serum LDL cholesterol and increase serum HDL cholesterol.
Research showed that a formulation of modified release niacin and with crystalline immediate-release niacin offered similar results.
Immediate-release tablets come dosages ranging from 50mg to 500mg. Initial dosing should be as low as possible to decrease adverse effect reactions and slowly titrated, preferably no more than 500 mg over four weeks to the patient’s response and tolerance.
Reverses in insulin resistance induced by lipid overload and rapid reduction of plasma FFA were observed with acute administration of niacin.
At the time of niacin administration, patients should avoid alcohol as it may increase the risk of pruritus and flushing. Niacin therapy is not a recommended pharmaceutical therapy in patients who are chronic alcohol abusers due to an increased risk of hepatotoxicity.
Oral dosage (nicotinic acid or nicotinamide/niacinamide)
Up to 500 mg/day orally, depending on the severity of niacin deficiency.
Intravenous or Intramuscular dosage
50 to 100 mg intramuscular five times daily, or 25 to 100 mg given by slow intravenous infusion twice daily, depending on the severity of niacin deficiency. Maximum: 500 mg/daily.
Dosing is up to 300 mg/day given by slow intravenous infusion, depending on the severity of niacin deficiency.
Hypercholesterolemia, mixed dyslipidemia or hypertriglyceridemia, type IV or V:
Dosing is 1500 to 3000 mg/day orally, divided either as two or three times daily.
Starting dose: 250 mg orally at bedtime, with a gradual increase of 250 mg/day every 4 to 7 days up to 2000 mg/day.
After two months, the dosage may be increased to 250 to 500 mg/day every 2 to 4weeks, with a maximum of 6000 mg/day.
Of note: 325 mg aspirin 30 minutes before a dose may reduce flushing;
Medication should be given without food.
Niacin is FDA Pregnancy Category C. When used at high doses to treat conditions such as dyslipidemia, niacin may cause harm to an unborn fetus.
Niacin has no black box warning.
The adverse effects of pharmacological doses of nicotinic acid are continuously under research in clinical research trials.
Some common reactions are:
Flushing: Niacin often causes generalized pruritus, and a burning sensation is usually limited to the face and chest and lasts 20 to 30 minutes. This side effect, however, is one that decreases not only in frequency but severity with time. Pretreatment of 30 minutes with aspirin (up to 325 mg) can be useful to counter this side effect. Laropiprant, a potent, selective antagonist of prostaglandin D2( PGD2)-receptor subtype-1 not only helps reduce this side effect of niacin but allows for optimal pharmacological dosing if needed.
One reaction to consider is niacin’s effects (whether used alone or in combination with statin medications) on glycemic control in patients with dyslipidemia, regardless of their diabetes mellitus status who are undergoing niacin therapy.
In non-diabetic patients with dyslipidemia, on average, five years of niacin therapy, whether used alone or in laropiprant combination therapy, was associated with a 34% increased risk of developing diabetes.
Other side effects include hyperuricemia, gastrointestinal disorders, rash, increase in homocysteine levels, hypotension, dyspepsia, elevations in AST and ALT, nausea, vomiting, and paresthesias.
Serious adverse reactions:
Peptic ulcer disease, arrhythmias, anaphylaxis, hepatotoxicity, hepatic necrosis, fulminant, macular edema.
Contraindications to niacin include the following conditions:
Laboratory monitoring is recommended in patients on niacin therapy due to its diverse side effects.
In pre-diabetes or diabetic patients, frequent monitoring of blood glucose is necessary as niacin can increase fasting blood glucose.
In patients on diabetic medications, such as acarbose, albiglutide, alogliptin, glipizide, or insulin, should also have blood glucose monitors as niacin has an antagonistic effect on blood glucose.
Niacin can cause an increase in uric acid, thus exerting an antagonist effect on medications for gout, such as pegloticase and allopurinol.
Niacin exerts an additive reaction with blood pressure medications (amlodipine clozapine, bisoprolol, diltiazem) opioids (morphine, oxycodone, tramadol, methadone) antipsychotics (quetiapine, risperidone) phosphodiesterase type 5 inhibitor (tadalafil) thus leading to hypotension. Frequent blood pressure checking is recommended. Also, niacin, in combination with some beta-blockers, may decrease its antihyperlipidemic efficacy.
Niacin can increase the risk of bleeding by exerting an additive effect. Niacin has shown to not only cause a reduction in platelet counts (mean of -11% with 2000 mg) but to increase prothrombin time (mean of approximately +4%), leading to bleeding, especially when combined with anticoagulants such as apixaban, caplacizumab, or warfarin. Thus, a blood coagulation panel should be a routine test.
Niacin also exerts an additive effect when combined with ceritinib, diazoxide leading to hyperglycemia.
Phosphorus levels also require monitoring in patients at risk for hypophosphatemia as niacin can cause a decrease in phosphorus levels (mean of -13% with 2000 mg).
Harm may result in a nursing baby as niacin can pass into breast milk; therefore, nursing mothers should avoid the drug.
In pharmacological doses (example 1000 to 3000 mg/day), flushing reaction associated with its crystalline nicotinic acid component (not nicotinamide) is the most common and studied the toxicity of niacin, which is both person-to-person and dose-dependent.
Other symptoms of toxicity may include dizziness, upset stomach, redness, itching, nausea, and vomiting.
Niacin is a pharmacotherapeutic pleiotropic agent with properties still yet to be fully understood. It is encouraged that individuals in the healthcare field (pharmacist, nurse practitioner, primary care provider) stay updated on niacin's properties and side effects uncovered by ongoing research. Niacin can cause flushing, a significant adverse impact that significantly affects its compliance in patients. Knowing how to titrate, from a minimal dose, will not only help minimize such unwanted effects but will surely benefit patient health outcomes. Close monitoring and periodic blood work on initiating or increasing the dosage of niacin should be obtained as it is known to increase the risk of bleeding, hypotension, hyperuricemia, and cause alterations in glycemic control. Its adverse effect on glycemic control in patients with dyslipidemia, both with or without diabetes, is one of its most concerning effects as it may cause diabetes in predisposed patients or make the management of diabetes a challenge.
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