Heparin preparations

Discuss the uses, general drug actions, adverse reactions, contraindications, precautions, and interactions of warfarin, heparin preparations, and the thrombolytic drugs. 

Promoting an Optimai Response to Therapy Heparin preparations, unlike warfarin, must be given by the parenteral route, preferably SC or IV The onset of anticoagiilation is almost immediate after a single dose. Maximum effects occur witiiin 10 minutes of administration. Clotting time will return to normal witiiin 4 hours unless subsequent doses are given. 

Monitoring and Managing Adverse Drug Reactions Bleeding at virtually any site can occur during tiierapy with any heparin preparation, even the LMWHs. The nurse monitors the patient s vital signs every 2 to 4 hours or as ordered by the primary health care provider. 

Commercial heparin preparations are also frequently bleached with oxidants (for example, KMn04 and H202),32 a treatment that must lead to some modification of their original structure and biological properties. 

The final yield and purity of a heparin preparation depend largely on the use of appropriate, analytical methods at different stages of extraction and purification. Heparin in tissue extracts is still most commonly determined biologically, by such assays as the U.S.P. assay for anticoagulant activity. It is now recognized10 that the anticoagulant activity does not measure the actual concentration of heparin (see also Sections XII and XIII). 

Among the spectroscopic methods applicable to polysaccharides, u.v. spectrophotometry is of little value for characterizing heparin, whose main, electronic chromophore (the C02 group) displays a band at 220 nm, that is, in a region where all glycosaminoglycans absorb (also through their N-acetyl chromophores), and where minor proportions of unsaturated or aromatic contaminants cause serious interference.77 With pure heparin preparations, the carboxylate chromophore is most useful for chiroptical measurements, and a semi-quantitative evaluation of the extent of N-acetylation of 2-amino-2-deoxy-D-glucose residues is also possible.78... 

As another criterion of purity, the amino acid content of heparins should be determined. This is usually performed by ion-exchange88 or liquid89 chromatographic analysis of hydrolyzates. Reasonably pure heparin preparations contain < 1% of total amino acids, mostly L-serine and glycine. Heparin preparations should also be analyzed for residual solvents, and analytical (as well as biological) data be expressed on a dry basis. (Heparins equilibrated with atmospheric humidity contain up to 15%, or even more, of water.) Unless volatile materials are completely removed or accounted for, elemental analyses of heparin are meaningless. 

Although the size distribution of fragments from heparinase (and hep-aranase) digests reflects the relative content of regular sequences 5 in different heparin preparations and fractions, these sequences may be quantitated only when the enzyme efficiency is high, and products are... 

In vitro platelet activation is dependent on the anticoagulant that is used for blood collection. In one study it was demonstrated that PF4 levels in platelet-poor plasma isolated after incubation without any stimuli for 1 hour at 37°C were as follows conventional heparin, 1180 ng/ml hirudin, 469 ng/ml citrate, 440 ng/ml and EDTA, 217 ng/ml (110). EDTA appears to suppress platelet degranulation. PF4 levels obtained with a low-molecular-weight heparin preparation called Frag-min were, however, comparable to those obtained with hirudin (110). 

These are prepared by enzymatic or chemical hydrolysis of conventional heparin, their molecular weight varies from 3,000 to 7,000. They are absorbed more completely than the conventional heparin preparation and having longer duration of action. 

Johnson EA, Mulloy B. The molecular weight range of mucosal heparin preparations. Carbohydr Res 1976 51 1 19-127. 

Subsequently, Howell improved the separation of heparin from protein by introducing the use of Lloyd s reagent (aluminum silicate) in acetic acid. The final stage then involved the precipitation of the heparin with excess barium hydroxide. Howell claimed that his heparin preparation con-... 

In 1933, Fischer and Schmitz first claimed to have isolated a pure heparin preparation. Their lengthy extraction and isolation procedure culminated in the isolation of a microcrystalline brucine salt 32 times as active as the starting material. No evidence other than that of appearance was quoted in support of the claimed crystallinity of the product. It was concluded that heparin was a carbohydrate (Molisch test) and contained a uronic acid. 

Fischer and Schmitz were also interested in the interaction of heparin with proteins, such as casein and serum albumin. They reported that heparin appeared to shift the isoelectric point of the proteins to the acid side, probably by the formation of a molecular complex, and that combination with the protein occurred only near the isoelectric point and on the acid side." The complex was reversibly dissociated by the addition of alkali. These results are of irnportance in selecting conditions for the purification of crude heparin preparations, and constitute the basis for the extraction procedure developed by Charles and Scott, which has subsequently been used extensively. 

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