Heparin

Description

Parnaparin sodium is a low molecular weight heparin obtained from bovine mucosal heparin by chemical depolymerization. It has more potent antithrombotic and profibrinolytic activity than heparin evidenced by its higher activity in inhibiting factor Xa and in reducing plasma activity of platelet activator inhibitor. It is effective in improving the venous blood outflow of lower limbs in deep vein thrombosis (DVT) patients in addition to preventing DVT following orthopaedic surgery, reportedly without causing bleeding complications. Parnaparin has also shown efficacy in inflammatory occlusive complications of postphlebitic syndrome and in acute myocardial infarction.

Chemical Properties

White or pale-colored amorphous powder; nearly odorless; hygroscopic. Soluble in water; insoluble in alcohol, benzene, acetone, chloroform, and ether; pH in 17% solution between 5.0 and 7.5.

Originator

Opocrin (Italy)

Occurrence

Heparin is a complex organic acid (mucopolysaccharide) present in mammalian tissues and a strong inhibitor of blood coagulation. Although the precise formula and structure of heparin are uncertain, it has been suggested that the formula for sodium heparinate, generally the form of the drug used in anticoagulant therapy, is (C12H16N2Na3)20 with a molecular weight of about 12,000. The commercial drug is derived from animal livers or lungs.

Uses

Medicine (anticoagulant), biochemical research, rodenticides.

Definition

heparin: A glycosaminoglycan (mucopolysaccharide)with anticoagulantproperties, occurring in vertebratetissues, especially the lungs andblood vessels.

Definition

A POLYSACCHARIDE that inhibits the formation of thrombin from prothrombin and thereby prevents the clotting of blood. It is used in medicine as an anticoagulant.

Definition

A complex organic acid (mucopolysaccharide) present in mammalian tissues; a strong inhibitor of blood coagulation; a dextrorotatory polysaccharide built up from hexosamine and hexuronic acid units containing sulfuric acid ester groups. Precise chemical fo

Manufacturing Process

5,000 pounds of beef intestine was introduced into a stainless steel reactor, jacketed with thermostated water and steam. 200 gallons of water and 10 gallons of chloroform were added. The mixture was agitated, the temperature was raised to 90°F and the agitation stopped. 5 gallons of toluene was added and the vessel closed. Autolysis was continued for 17 hours.
The extractant solution, consisting of 30 gallons of glacial acetic acid, 35 gallons of 30% aqueous ammonia, 50% sodium hydroxide to adjust the pH to 9.6 at 80°F and water to make 300 gallons, was added to the tissue. With agitation, the temperature was raised to 60°C and held there for 2 hours. Then steam was applied and the temperature was raised to boiling. 200 pounds of coarse filter aid (perlite) was added and the mixture filtered through a string discharge vacuum filter. The cake was washed with 200 gallons of hot water on the filter.
The filtrate was allowed to stand overnight and the fat skimmed off the top. After cooling to 100°F, the filtrate was transferred to a tank with thermostated water and the temperature set at 95° to 100°F. 24 gallons of pancreatic extract, prepared as described above, was added in 4-gallon increments every 12 hours for 3 days. The batch was brought to a boil and cooled to room temperature.
The batch was then filtered into a vessel and assayed for heparin content. 40,000,000 units were found in 1,000 gallons of filtrate. 20 kg of noctylamine was added and 105 pounds of glacial acetic acid was added to bring the pH to 6.5. 20 gallons of methyl isobutyl ketone was added and the whole mixture was vigorously agitated for 1 hour. The mixture was then allowed to stand overnight. The clear, aqueous phase was drained off and discarded. The grayish-brown interphase was then removed, together with a small amount of the ketone phase, and transferred into a small kettle. The interphase volume was 7 gallons.
30 gallons of methanol was added and the mixture warmed to 120°F and then the pH was adjusted to 9.0. The mixture was then allowed to settle overnight. The solids were collected with vacuum and washed with 5 gallons of methanol. The cake was then suspended in 5 gallons of water and the heparin precipitated with 10 gallons of methanol. The solids were collected under vacuum. The dry weight of the cake was 1,000 grams and the total units were 38,000,000, according to US Patent 2,884,358.

brand name

Liquaemin Sodium (Organon); Panheprin (Hospira);Fluxum.

Therapeutic Function

Anticoagulant

Biological Functions

Heparin (heparin sodium) is a mixture of highly electronegative acidic mucopolysaccharides that contain numerous N- and O-sulfate linkages. It is produced by and can be released from mast cells and is abundant in liver, lungs, and intestines.

Hazard

May cause internal bleeding.

Mechanism of action

The anticoagulation action of heparin depends on the presence of a specific serine protease inhibitor (serpin) of thrombin, antithrombin III, in normal blood.
Heparin binds to antithrombin III and induces a conformational change that accelerates the interaction of antithrombin III with the coagulation factors. Heparin also catalyzes the inhibition of thrombin by heparin cofactor II, a circulating inhibitor. Smaller amounts of heparin are needed to prevent the formation of free thrombin than are needed to inhibit the protease activity of clot-bound thrombin. Inhibition of free thrombin is the basis of low-dose prophylactic therapy.

Pharmacokinetics

The pharmacokinetic profiles of heparin and LMWHs are quite different. Whereas heparin is only 30% absorbed following subcutaneous injection, 90% of LMWH is systemically absorbed. The binding affinity of heparin to various protein receptors, such as those on plasma proteins, endothelial cells, platelets, platelet factor 4 (PF4), and macrophages, is very high and is related to the high negative-charged density of heparin. This high nonspecific binding decreases bioavailability and patient variability. Additionally, heparin's nonspecific binding may account for heparin's narrow therapeutic window and heparin-induced thrombocytopenia (HIT), a major limitation of heparin. These same affinities are quite low, however, in the case of LMWHs. These parameters explain several of the benefits of the LMWH's. The favorable absorption kinetics and low protein binding affinity of the LMWHs results in a greater bioavailability compared with heparin. The lowered affinity of LMWHs for PF4 seems to correlate with a reduced incidence of HIT. Heparin is subject to fast zero-order metabolism in the liver, followed by slower first-order clearance from the kidneys. The LMWHs are renally cleared and follow first-order kinetics. This makes the clearance of LMWHs more predictable as well as resulting in a prolonged half-life. Finally, the incidence of heparin-mediated osteoporosis is significantly diminished with use of LMWHs as opposed to heparin.

Pharmacology

The physiological function of heparin is not completely understood. It is found only in trace amounts in normal circulating blood. It exerts an antilipemic effect by releasing lipoprotein lipase from endothelial cells; heparinlike proteoglycans produced by endothelial cells have anticoagulant activity. Heparin decreases platelet and inflammatory cell adhesiveness to endothelial cells, reduces the release of platelet-derived growth factor, inhibits tumor cell metastasis, and exerts an antiproliferative effect on several types of smooth muscle.
Therapy with heparin occurs in an inpatient setting. Heparin inhibits both in vitro and in vivo clotting of blood. Whole blood clotting time and activated partial thromboplastin time (aPTT) are prolonged in proportion to blood heparin concentrations.

Side effects

The major adverse reaction resulting from heparin therapy is hemorrhage. Bleeding can occur in the urinary or gastrointestinal tract and in the adrenal gland. Subdural hematoma, acute hemorrhagic pancreatitis, hemarthrosis, and wound ecchymosis also occur. The incidence of life-threatening hemorrhage is low but variable. Heparin-induced thrombocytopenia of immediate and delayed onset may occur in 3 to 30% of patients. The immediate type is transient and may not involve platelet destruction, while the delayed reaction involves the production of heparin-dependent antiplatelet antibodies and the clearance of platelets from the blood. Heparin-associated thrombocytopenia may be associated with irreversible aggregation of platelets (white clot syndrome). Additional untoward effects of heparin treatment include hypersensitivity reactions (e.g., rash, urticaria, pruritus), fever, alopecia, hypoaldosteronism, osteoporosis, and osteoalgia.

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: increased risk of bleeding with NSAIDs - avoid concomitant use with IV diclofenac; increased risk of haemorrhage with ketorolac - avoid.
Nitrates: anticoagulant effect reduced by infusions of glyceryl trinitrate.
Use with care in patients receiving oral anticoagulants, platelet aggregation inhibitors, aspirin or dextran.

Metabolism

Heparin is prescribed on a unit (IU) rather than milligram basis. The dose must be determined on an individual basis. Heparin is not absorbed after oral administration and therefore must be given parenterally. Intravenous administration results in an almost immediate anticoagulant effect. There is an approximate 2-hour delay in onset of drug action after subcutaneous administration. Intramuscular injection of heparin is to be avoided because of unpredictable absorption rates, local bleeding, and irritation. Heparin is not bound to plasma proteins or secreted into breast milk, and it does not cross the placenta.
Heparin’s action is terminated by uptake and metabolism by the reticuloendothelial system and liver and by renal excretion of the unchanged drug and its depolymerized and desulfated metabolite. The relative proportion of administered drug that is excreted as unchanged heparin increases as the dose increases. Renal insufficiency reduces the rate of heparin clearance from the blood.

Purification Methods

Most likely contaminants are mucopolysaccharides including heparin sulfate and dermatan sulfate. Purify heparin by precipitation with cetylpyridinium chloride from saturated solutions of high ionic strength. [Cifonelli & Roden Biochemical Preparations 12 12 1968, Wolfrom et al. J Org Chem 29 540 1946, Huggard Adv Carbohydr Chem 10 336-368 1955]