Nicotinic Acid Actions
Nicotinic Acid binds to Nicotinate D-ribonucleotide phyrophsopate phosphoribosyltransferase, Nicotinic acid phosphoribosyltransferase, Nicotinate N-methyltransferase and the Nicotinic Acid receptor. Nicotinic Acid is the precursor to nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are vital cofactors for dozens of enzymes. The mechanism by which Nicotinic Acid exerts its lipid lowering effects is not entirely understood, but may involve several actions, including a decrease in esterification of hepatic triglycerides. Nicotinic Acid treatment also decreases the serum levels of apolipoprotein B-100 (apo B), the major protein component of the VLDL (very low-density lipoprotein) and LDL fractions.
Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.
Nicotinic Acid is sometimes taken at bedtime with a low-fat snack. Follow your doctor's instructions.
Nicotinic Acid can cause certain side effects, such as flushing (warmth, itching, redness, or tingly feeling under your skin). These effects can be made worse if you drink alcohol or hot beverages shortly after you take Nicotinic Acid. These effects should disappear over time as you keep taking the medication.
Take Nicotinic Acid with a full glass of cold or cool water. Taking the medication with a hot drink may increase your risk of side effects such as flushing.
Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.
Nicotinic Acid extended-release tablets and capsules contain higher strengths of the medicine than the regular Nicotinic Acid tablets. Take only the dose that is correct for the type of Nicotinic Acid tablet or capsule you are using.
Nicotinic Acid can cause you to have unusual results with certain medical tests (urine tests). Tell any doctor who treats you that you are using Nicotinic Acid.
If you stop taking Nicotinic Acid for any length of time, talk with your doctor before starting the medication again. You may need to restart the medication at a lower dose.
While using Nicotinic Acid, you may need blood tests at your doctor's office. Your kidney or liver function may also need to be checked. Visit your doctor regularly.
Nicotinic Acid is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.
Store at room temperature away from moisture and heat.
Administer with food. To attenuate flushing symptoms, may premedicate with aspirin 30 minutes before dose; avoid ingestion of alcohol, hot or spicy foods/liquids concurrently with Nicotinic Acid. May also use other nonsteroidal anti-inflammatory drugs to prevent flushing according to the manufacturer.
Niaspan: Administer at bedtime after a low-fat snack. Two of the 500 mg and one of the 1,000 mg tablet strengths are interchangeable, but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable. When switching from IR tablet, initiate Niaspan with the recommended titration schedule. If therapy is interrupted for an extended period, dose should be retitrated.
Long-acting forms should not be crushed, broken, or chewed. Slo-Nicotinic Acid may be broken along the score line. Do not substitute long-acting forms for immediate release ones.
Bariatric surgery: Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER formulations should be swallowed whole. Do not chew or crush. If safety and efficacy of Nicotinic Acid can be effectively monitored, no change in formulation or administration is required after bariatric surgery. Bariatric vitamin supplementation is recommended on a lifelong basis after surgery; consider integration of daily Nicotinic Acid regimen into the bariatric vitamin regimen.
The mechanism by which Nicotinic Acid alters lipid profiles has not been well defined. It may involve several actions including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity, which may increase the rate of chylomicron triglyceride removal from plasma. Nicotinic Acid decreases the rate of hepatic synthesis of VLDL and LDL, and does not appear to affect fecal excretion of fats, sterols, or bile acids.
Due to extensive and saturable first-pass metabolism, Nicotinic Acid concentrations in the general circulation are dose dependent and highly variable. Time to reach the maximum Nicotinic Acid plasma concentrations was about 5 hours following Nicotinic Acid extended-release tablets. To reduce the risk of gastrointestinal (GI) upset, administration of Nicotinic Acid extended-release tablets with a low-fat meal or snack is recommended.
Single-dose bioavailability studies have demonstrated that the 500 mg and 1000 mg tablet strengths are dosage form equivalent but the 500 mg and 750 mg tablet strengths are not dosage form equivalent.
The pharmacokinetic profile of Nicotinic Acid is complicated due to extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form nicotinuric acid (NUA). NUA is then excreted in the urine, although there may be a small amount of reversible metabolism back to Nicotinic Acid. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is further metabolized to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans. At the doses used to treat hyperlipidemia, these metabolic pathways are saturable, which explains the nonlinear relationship between Nicotinic Acid dose and plasma concentrations following multiple-dose Nicotinic Acid extended-release tablet administration.
Nicotinamide does not have hypolipidemic activity; the activity of the other metabolites is unknown.
Following single and multiple doses, approximately 60 to 76% of the Nicotinic Acid dose administered as Nicotinic Acid extended-release tablets was recovered in urine as Nicotinic Acid and metabolites; up to 12% was recovered as unchanged Nicotinic Acid after multiple dosing. The ratio of metabolites recovered in the urine was dependent on the dose administered.
No pharmacokinetic studies have been performed in this population (≤ 16 years).
No pharmacokinetic studies have been performed in this population (> 65 years).
No pharmacokinetic studies have been performed in this population. Nicotinic Acid extended-release tablets should be used with caution in patients with renal disease.
No pharmacokinetic studies have been performed in this population. Active liver disease, unexplained transaminase elevations and significant or unexplained hepatic dysfunction are contraindications to the use of Nicotinic Acid extended-release tablets.
Steady-state plasma concentrations of Nicotinic Acid and metabolites after administration of Nicotinic Acid extended-release tablets are generally higher in women than in men, with the magnitude of the difference varying with dose and metabolite. This gender difference observed in plasma levels of Nicotinic Acid and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution. Recovery of Nicotinic Acid and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both genders.
Nicotinic Acid did not affect fluvastatin pharmacokinetics.
When Nicotinic Acid extended-release tablets 2000 mg and lovastatin 40 mg were co-administered, Nicotinic Acid extended-release tablets increased lovastatin Cmax and AUC by 2% and 14%, respectively, and decreased lovastatin acid Cmax and AUC by 22% and 2%, respectively. Lovastatin reduced Nicotinic Acid extended-release tablet bioavailability by 2 to 3%.
When Nicotinic Acid extended-release tablets 2000 mg and simvastatin 40 mg were co-administered, Nicotinic Acid extended-release tablets increased simvastatin Cmax and AUC by 1% and 9%, respectively, and simvastatin acid Cmax and AUC by 2% and 18%, respectively. Simvastatin reduced Nicotinic Acid extended-release tablet bioavailability by 2%.
Bile Acid Sequestrants
An in vitro study was carried out investigating the Nicotinic Acid-binding capacity of colestipol and cholestyramine. About 98% of available Nicotinic Acid was bound to colestipol, with 10 to 30% binding to cholestyramine.
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Information checked by Dr. Sachin Kumar, MD Pharmacology