Heparin sodium

Absorption

Subcutaneous injection - about 90% when measured as anti-Xa activity versus 67% for anti-IIa activity.

Toxicity

Osteoporosis with increasing duration of use, bleeding, alopecia, heparin induced thrombocytopenia (HIT). All of these adverse drug reactions occur less with LMWH compared to unfractionated heparin. Tinzaparin showed no toxic effects at doses up to 5 mg/kg in mice, rats, or dogs in standard acute, subacute, and chronic toxicity studies.

Description

Reviparin sodium, a second-generation low molecular weight heparin produced from porcine mucosal heparin, has been introduced for the prevention of deep vein thrombosis and pulmonary embolism following surgery. It has sustained activity and increased bioavailability over unfractioned heparin. More noticeably, reviparin shows a pronounced inhibitory effect, both in vitro and in vivo , on smooth muscle cell proliferation which plays a predominant role in restenosis following angioplasty. Indeed, a lower incidence of restenosis without major bleeding complications has been reported for reviparin treated patients who successfully underwent percutaneous transluminal coronary angioplasty.

Chemical properties

off-white powder

Originator

Knoll (Germany)

The Uses of Heparin sodium

Heparin sodium salt is used as a blood anti-coagulant. It is also used as an effective inhibitor of mesenchymal cell proliferation. Further, it binds to antithrombin III, which inhibits coagulation proteases. It is used as a major component of serum free media for preventing cell aggregation. It is also used as an anti-cancer agent in in vitro cancer research.

The Uses of Heparin sodium

for coagulation proteins, nucleic acids

The Uses of Heparin sodium

corrosive moisture sensitive

Background

Reviparin is a low molecular weight heparin which seems to have a better safety profile than unfractionated heparin. It is prepared from porcine intestinal mucosa by nitrous acid depolymerization. Reviparin has a molecular weight of 3.9 kDa. It was developed by Abbott laboratories and in 2009, reviparin presented an orphan drug designation by the FDA.

Indications

By the FDA, reviparin is indicated for the treatment of deep vein which may lead to pulmonary embolism in pediatric patients. It is also indicated for the long-term treatment of acute deep vein thrombosis with or without pulmonary embolism in pregnant patients.

Background

Tinzaparin is a low molecular weight heparin (LMWH), produced by enzymatic depolymerization of unfractionated heparin from porcine intestinal mucosa. It is a heterogeneous mixture of with an average molecular weight between 5500 and 7500 daltons. Tinzaparin is composed of molecules with and without a special site for high affinity binding to antithrombin III (ATIII). This complex greatly accelerates the inhibition of factor Xa. It is an anticoagulant and considered an antithrombotic. Tinzaparin must be given either subcutaneously or parenterally. LMWHs are less effective at inactivating factor IIa due to their shorter length compared to unfractionated heparin.

Indications

Tinzaparin is used for the prevention of postoperative venous thromboembolism in patients undergoing orthopedic surgery and in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism. It is also used for the treatment of deep vein thrombosis and/or pulmonary embolism. It is indicated for use in preventing clot formation in indwelling intravenous lines for hemodialysis.

What are the applications of Application

Heparin sodium salt is a heparin polymer that produces its anticoagulant effect by activating ATIII (antithrombin)

Manufacturing Process

Heparinic acid a highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts.
In a self-regulated process for depolymerizing a heparin in an aqueous solution by providing about 0.02 to 0.1 M nitrous acid and a pH of about 2 to 3 in said solution, so that process occurs when all the nitrous acid has been consumed and mucopolysaccharides are produced from the heparin having an average molecular weight of less than 6,000. Heparin has molecular weight from 2000 to 50000. The products obtained by a below described method are constituted by a major part of species of molecular weight of about 2,000 to 8,000, which corresponds to structures having from about 8 to 40 saccharide entities (the molecular weights are measured by the HPLC method, by means, for example, of a 0.5 M sodium sulphate buffer).
Self-Regulated Depolymerization of Heparin and Production of MPS of Low Molecular Weight.
Into 15 liters of distilled water at +20°C, 1,500 grams of commercial heparin having a YW/USP ratio in the vicinity of 1 and a USP titer of 160 iu, are dissolved. 51.8 g of sodium nitrate dissolved in 300 ml of distilled water are added, and immediately the pH is lowered to 2.5 by pure hydrochloric acid.
The reaction then takes place and its progress is checked until the absence of nitrous ions. After 40 minutes, the presence or absence of nitrous ions is checked at regular intervals in the reaction medium. Starch-iodine paper, for example, is used, checking every 5 minutes. After about 60 minutes of reaction, the nitrous acid had been entirely consumed and no more NO2 - ions remained in the reaction medium. The pH was then adjusted to 7 with pure caustic soda, and the products of the reaction were recovered by the addition of 31 liters of pure ethanol (2 volumes). The precipitate formed was collected by centrifugation, washed with ethanol and dried at 60°C under vacuum. 1,200 g of products having the following characteristics were collected: USP titer: 19 μ/mg; APTT titer: 13 μ/mg; Yin and Wessler titer: 202 μ/mg.
In 10 liters of distilled water, at room temperature (15°-20°C) 1,000 grams of commercial injectable heparin having a USP titer of 170 μ/mg and a YW titer of 160 μ/mg, are dissolved. 38 g of sodium nitrite (final molarity 0.055 M) dissolved in 200 ml of water, is added. The pH is immediately lowered to 2.5 by pure hydrochloric acid. The reaction is checked as above at regular intervals of time (5-10 minutes). After 30 minutes, NO2 - ions are no longer detected in the reaction medium. The pH is then adjusted to 7 with 5 N soda; the products of the reaction are recovered by the addition of 21 liters of pure ethanol (2 volumes). The precipitate formed is collected by centrifugation, washed with ethanol and dried at 60°C under vacuum. Finally there are obtained 780 grams of white coloured powder having the following characteristics: USP Titer: 22 μ/mg; Yin and Wessler Titer: 260 μ/mg; APTT Titer: 10 μ/mg. Content of nitrites-nitrates: 5 ppm: <4 ppm. Average molecular weight: less than 6,000. Percentage of species whose molecular weight exceeds 10,000: less than 1%.

brand name

Normiflo (Pharmacia & Upjohn);Clivarin.

Therapeutic Function

Anticoagulant, Antithrombotic

General Description

Heparin is mainly responsible for the delay in the coagulation of blood. It enhances the antithrombin-mediated inactivation of proteases in the coagulation pathway.

Pharmacokinetics

Reviparin is been shown to present significant inhibition of smooth muscle cell migration and proliferation in human cell cultures without affecting endothelial cell growth.

Pharmacokinetics

Tinzaparin, like other LMWHs, have a higher anti-Xa activity than anti-IIa activity. The anti-Xa activity of tinzaparin is 2.0 +/- 0.5 times greater than its to anti-IIa activity. Heparin exhibits approximately equal inhibitory activity against Xa and IIa. Tinzaparin is an anticoagulant that blocks the formation of thrombi. Like all LMWHs, tinzaparin only causes activated partial thromboplastin time (aPTT) prolongation at higher doses and routine monitoring is not recommended. However, anti-factor Xa levels may be monitored in some conditions such as pregnancy and renal dysfunction. Its use should be avoided in patients with a creatinine clearance less than 20 mL/min. In these patients, unfractionated heparin should be used. Tinzaparin can be used in patients who have a creatinine clearance between 20-30 mL/min, giving it the highest safety threshold for use in renal failure patients compared to all the LMWHs.

Veterinary Drugs and Treatments

Heparin’s primary uses in small animal medicine has included treatment of Disseminated Intravascular Coagulation (DIC) and prophylaxis of thromboembolic disease. In horses, it has been used in the treatment of DIC and as prophylactic therapy for laminitis (unproven efficacy).
Use for treating DIC has become increasingly controversial. The most recent evidence suggests that heparin not be used during DIC in patients with concurrent inflammatory processes.

Metabolism

Not Available

Metabolism

Sulfation and polymerization occurs in the liver.

storage

Desiccate at RT

Purification Methods

Dissolve the salt in 0.1M NaCl (1g/100mL) and precipitate it by additing EtOH (150mL). [Wolfrom et al. J Org Chem 29 540 1946, Huggard Adv Carbohydr Chem 10 336-368 1955.]