3-carboxypyridine

Uses

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atheroscleroticvascular disease due to hyperlipidemia. 3-carboxypyridine therapy is used for an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

• 3-carboxypyridine is used to reduce elevated TC, LDL-C, Apo B and TG levels, and to increase HDL-C in patients with primary hyperlipidemia and mixed dyslipidemia.
• In patients with a history of myocardial infarction and hyperlipidemia, niacin is used to reduce the risk of recurrent nonfatal myocardial infarction.
• In patients with a history of coronary artery disease (CAD) and hyperlipidemia, niacin, in combination with a bile acid binding resin, is used to slow progression or promote regression of atherosclerotic disease.
• 3-carboxypyridine in combination with a bile acid binding resin is used to reduce elevated TC and LDL-C levels in adult patients with primary hyperlipidemia.
• 3-carboxypyridine is also used as adjunctive therapy for treatment of adult patients with severe hypertriglyceridemia who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort to control them.

3-carboxypyridine is also used to associated treatment for these conditions: Atherosclerosis, Mixed Dyslipidemias, Myocardial Infarction, Pellagra, Vitamin Deficiency, Primary Hyperlipidemia, Severe Hyperlipidemia, Dietary supplementation

How 3-carboxypyridine works

3-carboxypyridine performs a number of functions in the body and so has many mechanisms, not all of which have been fully described. 3-carboxypyridine can decrease lipids and apolipoprotein B (apo B)-containing lipoproteins by modulating triglyceride synthesis in the liver, which degrades apo B, or by modulating lipolysis in adipose tissue.

3-carboxypyridine inhibits hepatocyte diacylglycerol acyltransferase-2. This action prevents the final step of triglyceride synthesis in hepatocytes, limiting available triglycerides for very low density lipoproteins (VLDL). This activity also leads to intracellular degradation of apo B and decreased production of low density lipoproteins, the catabolic product of VLDL.

3-carboxypyridine also inhibits a high density lipoprotein (HDL) catabolism receptor, which increases the levels and half life of HDL.

Dosage

3-carboxypyridine dosage

3-carboxypyridine can be administered as a single dose at bedtime, after a snack or meal and doses should be individualized according to patient response. Therapy with 3-carboxypyridine must be initiated at 500 mg in order to reduce the incidence and severity of side effects which may occur during early therapy.

Maintenance Dose: The daily dosage of 3-carboxypyridine should not be increased by more than 500 mg in any 4-week period. The recommended maintenance dose is 1000 mg (two 500 mg tablets or one 1000 mg tablet) to 2000 mg (two 1000 mg tablets or four 500 mg tablets) once daily at bedtime. Doses greater than 2000 mg daily are not recommended. Women may respond at lower 3-carboxypyridine doses than men.

Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable.

Flushing of the skin may be reduced in frequency or severity by pretreatment with aspirin (up to the recommended dose of 325 mg taken 30 minutes prior to 3-carboxypyridine dose). Tolerance to this flushing develops rapidly over the course of several weeks. Flushing,pruritus, andgastrointestinaldistress are also greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of 3-carboxypyridine ingestion.

Equivalent doses of 3-carboxypyridine should not be substituted for sustained-release (modified-release, timed-release) niacin preparations or immediate-release (crystalline) niacin. Patients previously receiving other niacin products should be started with the recommended 3-carboxypyridine titration schedule, and the dose should subsequently be individualized based on patient response.

If 3-carboxypyridine therapy is discontinued for an extended period, reinstitution of therapy should include a titration phase.

3-carboxypyridine tablets should be taken whole and should not be broken, crushed or chewed before swallowing.

Side Effects

3-carboxypyridine is generally well tolerated; adverse reactions have been mild and transient.The most frequent advers effects were flushing, itching, pruritis, nausea and GI upset, jaundice ,hypotension, tachycardia, increased serum blood glucose and uric acid levels, myalgia.

Toxicity

Overdose of niacin may present with severe prolonged hypotension. Patients experiencing an overdose should be treated with supportive measures which may include intravenous fluids.

The oral LD₅₀ in the mouse is 3720mg/kg, in the rabbit is 4550mg/kg, in the rat is 7000mg/kg, and the dermal LD₅₀ in the rat is >2000mg/kg.

Precaution

Before instituting therapy with 3-carboxypyridine, an attempt should be made to control hyperlipidemia with appropriate diet, exercise, and weight reduction in obese patients and to treat other underlying medical problems. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during 3-carboxypyridine therapy. Frequent monitoring of liver function tests and blood glucose should be performed to ascertain that the drug is producing no adverse effects on these organ systems. Diabetic patients may experience a dose-related rise in glucose intolerance, the clinical significance of which is unclear. Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycemic therapy may be necessary.

Caution should also be used when 3-carboxypyridine is used in patients with unstable angina or in the acute phase of MI, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers or adrenergic blocking agents. Elevated uric acid levels have occurred with 3-carboxypyridine therapy, therefore use with caution in patients predisposed to gout. 3-carboxypyridine has been associated with small but statistically significant dose-related reductions in platelet count and increases in prothrombin time. Caution should be observed when 3-carboxypyridine is administered concomitantly with anticoagulants; prothrombin time and platelet counts should be monitored closely in such patients. 3-carboxypyridine has been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg). So phosphorus levels should be monitored periodically in patients at risk.

Interaction

3-carboxypyridine may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension. Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this finding is unclear. About 98% of available 3-carboxypyridine was bound to colestipol, with 10 to 30% binding to cholestyramine. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of 3-carboxypyridine.

Food Interaction

• Avoid alcohol. Alcohol increases the chances of flushing and pruritus.
• Take with food. Food reduces GI upset and irritation.

3-carboxypyridine Alcohol interaction

[Moderate] GENERALLY AVOID:

Ethanol can exacerbate the cutaneous flushing that is a common side effect of niacin.

At least one case of delirium and lactic acidosis has been reported with coadministration of these drugs, although data are limited.

Coadministration should probably be discouraged, particularly since chronic consumption of large amounts of alcohol is associated with hyperlipidemia.

3-carboxypyridine Drug Interaction

Major: rosuvastatin, atorvastatinMinor: aspirin, aspirinUnknown: calcium / vitamin d, ubiquinone, duloxetine, omega-3 polyunsaturated fatty acids, metoprolol, omega-3 polyunsaturated fatty acids, clopidogrel, levothyroxine, acetaminophen, cyanocobalamin, pyridoxine, ascorbic acid, cholecalciferol, alprazolam, zinc sulfate, cetirizine

3-carboxypyridine Disease Interaction

Major: coronary artery disease, hepatotoxicity, hypotension, peptic ulcer diseaseModerate: hyperglycemia, hyperuricemia

Volume of Distribution

Data regarding the volume of distribution of niacin is not readily available.

Elimination Route

In patients with chronic kidney disease, the C_max is 0.06µg/mL for a 500mg oral dose, 2.42µg/mL for a 1000mg oral dose, and 4.22µg/mL for a 1500mg oral dose. The T_max is 3.0 hours for a 1000mg or 1500mg oral dose. The AUC is 1.44µg*h/mL for a 500mg oral dose, 6.66µg*h/mL for a 1000mg oral dose, and 12.41µg*h/mL for a 1500mg oral dose. These values did not drastically differ in patients requiring dialysis.

Half Life

The half life of niacin is 0.9h, nicotinuric acid is 1.3h, and nicotinamide is 4.3h.

Clearance

Data regarding the clearance of niacin is not readily available.

Elimination Route

69.5% of a dose of niacin is recovered in urine. 37.9% of the recovered dose was N-methyl-2-pyridone-5-carboxamide, 16.0% was N-methylnicotinamide, 11.6% was nicotinuric acid, and 3.2% was niacin.

Pregnancy & Breastfeeding use

3-carboxypyridine cannot be used in pregnancy and lactation because of a lack of information.

Contraindication

3-carboxypyridine is contraindicated in patients with a known hypersensitivity to 3-carboxypyridine or any component of this medication, significant or unexplained hepatic dysfunction, active peptic ulcer disease or arterial bleeding.

Acute Overdose

Supportive measures should be undertaken in the event of an overdosage. Symptoms may include nausea, dizziness, itching, vomiting, upset stomach, and flushing

Innovators Monograph

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