HEPARIN SODIUM, HEPARIN CALCIUM

Chemistry - Heparin is an anionic, heterogeneous sulfated glycosaminoglycan molecule with anaverage molecular weight of 12, 000 that is found naturally in mast cells. It is available commerciallyas either sodium or calcium salts and is obtained from either porcine intestinal mucosa (bothcalcium and sodium salts) or from bovine lung tissue (sodium salt only). Heparin sodium andcalcium occur as white or pale-colored, amorphous, hygroscopic powders having a faint odor. Bothare soluble in water and practically insoluble in alcohol; the commercial injections have a pH of 5-7.5. Heparin potency is expressed in terms of USP Heparin units and values are obtained bycomparing against a standard reference from the USP. The USP requires that potencies be not lessthan 120 units/mg on a dried basis for heparin derived from lung tissue, and 140 units/mg whenderived from all other tissue sources.

Storage, Stability, Compatibility

Heparin solutions should be stored at room temperature (15-30°C) and not frozen. Avoid excessive exposure to heat.
Heparin sodium is reportedly compatible with the following intravenous solutions and drugs:amino acids 4.25%-dextrose 25%, dextrose-Ringer's combinations, dextrose-lactated Ringer'ssolutions, fat emulsion 10%, Ringer's injection, Normosol R, aminophylline, amphotericin B w/ orw/o hydrocortisone sodium phosphate, ascorbic acid injection, bleomycin sulfate, calcium gluconate, cephapirin sodium, chloramphenicol sodium succinate, clindamycin phosphate, dimenhydrinate, dopamine HCl, erythromycin gluceptate, isoproterenol HCl, lidocaine HCl, methylprednisolonesodium succinate, metronidazole with sodium succinate, nafcillin sodium, norepinephrine bitartrate, potassium chloride, prednisolone sodium succinate, promazine HCl, sodium bicarbonate, verapamil
HCl and vitamin B-complex w/ or w/o vitamin C.
Heparin compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: dextrose-saline combinations, dextrose in water, lactated
Ringer's injection, saline solutions, ampicillin sodium, cephalothin sodium, dobutamine HCl, hydrocortisone sodium succinate, methicillin sodium, oxytetracycline HCl, penicillin Gsodium/potassium, and tetracycline HCl. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references formore specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).
Heparin sodium is reported incompatible with the following solutions or drugs: sodium lactate1/6 M, amikacin sulfate, chlorpromazine HCl, codeine phosphate, cytarabine, daunorubicin HCl, diazepam, doxorubicin HCl, droperidol HCl w/ & w/o fentanyl citrate, erythromycin lactobionate, gentamicin sulfate, hyaluronidase, kanamycin sulfate, levorphanol bitartrate, meperidine HCl, methadone HCl, morphine sulfate, pentazocine lactate, phenytoin sodium, polymyxin B sulfate, streptomycin sulfate and vancomycin HCl.

Pharmacology - HEPARIN SODIUM, HEPARIN CALCIUM

Heparin acts on coagulation factors in both the intrinsic and extrinsic coagulationpathways. Low concentrations of heparin when combined with antithrombin III inactivate factor Xaand prevent the conversion of prothrombin to thrombin. In higher doses, heparin inactivatesthrombin, blocks the conversion of fibrinogen to fibrin and when combined with antithrombin IIIinactivates factors IX, X, XI, XII. By inhibiting the activation of factor XIII (fibrin stabilizing factor), heparin also prevents the formation of stable fibrin clots. While heparin will inhibit the reactionsthat lead to clotting, it does not significantly change the concentrations of clotting factors. Heparindoes not lyse clots, but can prevent the growth of existing clots.
Heparin also causes increased release of lipoprotein lipase, thereby increasing the clearance ofcirculating lipids and increasing plasma levels of free fatty acids.

Uses, Indications

Heparin's primary uses in small animal medicine include treatment of
Disseminated Intravascular Coagulation (DIC), and treatment of thromboembolic disease. Inhorses, it has also been used in the treatment of DIC and as prophylactic therapy for laminitis(unproven efficacy).

Pharmacokinetics - HEPARIN SODIUM, HEPARIN CALCIUM

Heparin is not absorbed by the gut if administered orally and must be givenparenterally to be effective. Anticoagulant activity begins immediately after direct IV bolus injection, but may take up to one hour after deep SQ injection. When heparin is given by continuous IVinfusion, an initial bolus must be administered for full anticoagulant activity to begin.
Heparin is extensively protein bound, primarily to fibrinogen, low-density lipoproteins andglobulins. It does not appreciably cross the placenta or enter milk.
Heparin's metabolic fate is not completely understood. The drug is apparently partially metabolized by the liver and also inactivated by the reticuloendothelial system. Serum half-lives in humans average 1-2 hours.

Contraindications, Precautions, Reproductive Safety

Heparin is contraindicated in patientshypersensitive to it, have severe thrombocytopenia or uncontrollable bleeding (caused by somethingother than DIC). One author (Green 1989) states that with DIC "heparin should not be given toactively bleeding patients that have severe factor depletion and thrombocytopenia, as fatalhemorrhage may result."
Do not administer IM, as heparin may cause hematoma formation. Hematomas, pain, and irritationmay also occur after deep SQ dosing.
While heparin does not cross the placenta and is generally felt to be the anticoagulant of choiceduring pregnancy, its safe use in pregnancy has not been firmly established and pregnancy outcomes may be unfavorable. It should be used cautiously and only when clearly necessary.

Adverse Effects, Warnings

Bleeding and thrombocytopenia are the most common adverse effects associated with heparin therapy. Because heparin is derived from bovine or porcine tissues, hypersensitivity reactions may be possible. Less commonly encountered adverse effects that havebeen reported in animals and/or humans include vasospastic reactions (after several days of therapy), osteoporosis and diminished renal function (after long-term, high-dose therapy), rebound hyperlipidemia, hyperkalemia, alopecia, suppressed aldosterone synthesis and priapism.

Overdosage, Acute Toxicity

Overdosage of heparin is associated with bleeding. Symptoms thatcould be seen before frank bleeding occurs may be manifested by hematuria, tarry stools, petechiae, bruising, etc. Protamine can reverse heparin's effects; see the Protamine monograph for moreinformation.

Drug Interactions

Use heparin with caution with other drugs that can cause changes in coagulation status or platelet function (e.g., aspirin, phenylbutazone, dipyridamole, warfarin, etc.);more intensive monitoring may be indicated.
Heparin may antagonize the actions of corticosteroids, insulin or ACTH.
Heparin may increase plasma levels of diazepam.
Antihistamines, intravenous nitroglycerin, propylene glycol, digoxin, and tetracyclinesmay partially counteract the actions of heparin.
Drug/Laboratory Interactions - Unless heparin is administered by continuous infusion, it canalter prothrombin time (PT) which can be misleading in patients also receiving a coumarin or anindandione anticoagulant.
Heparin can interfere with the results of the BSP (sulfobromophthaelein, bromosulfophthalein)test by changing the color intensity of the dye and shifting the absorption peak from 580 nm to 595nm.
Heparin can cause falsely elevated values of serum thyroxine if using competitive proteinbinding methods of determination. Radioimmunoassay (RIA) and protein bound iodine methodsare apparently unaffected by heparin.
When heparin is used as an anticoagulant in vitro (e.g., in blood collection containers), white cellcounts should be performed within 2 hours of collection. Do not use heparinized blood forplatelet counts, erythrocyte sedimentation rates, erythrocyte fragmentation tests, or for anytests involving complement or isoagglutinins. Errors in blood gas determinations for CO2pressure, bicarbonate concentration or base excess may occur if heparin encompasses 10% or moreof the blood sample.