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Chemistry – Heparin is an anionic, heterogeneous sulfated glycosaminoglycan molecule with an average molecular weight of 12,000 that is found naturally in mast cells. It is available commercially as either sodium or calcium salts and is obtained from either porcine intestinal mucosa (both calcium and sodium salts) or from bovine lung tissue (sodium salt only). Heparin sodium and calcium occur as white or pale-colored, amorphous, hygroscopic powders having a faint odor. Both are 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 by comparing against a standard reference from the USP. The USP requires that potencies be not less than 120 units/mg on a dried basis for heparin derived from lung tissue, and 140 units/mg when derived 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’s solutions, fat emulsion 10%, Ringer’s injection, Normosol R, aminophylline, amphotericin B w/ or w/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, methylprednisolone sodium 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 G sodium/potassium, and tetracycline HCl. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).
Heparin sodium is reported incompatible with the following solutions or drugs: sodium lactate 1/6 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 acts on coagulation factors in both the intrinsic and extrinsic coagulation pathways. Low concentrations of heparin when combined with antithrombin III inactivate factor Xa and prevent the conversion of prothrombin to thrombin. In higher doses, heparin inactivates thrombin, blocks the conversion of fibrinogen to fibrin and when combined with antithrombin III inactivates 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 reactions that lead to clotting, it does not significantly change the concentrations of clotting factors. Heparin does not lyse clots, but can prevent the growth of existing clots.
Heparin also causes increased release of lipoprotein lipase, thereby increasing the clearance of circulating 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. In horses, it has also been used in the treatment of DIC and as prophylactic therapy for laminitis (unproven efficacy).
Pharmacokinetics – Heparin is not absorbed by the gut if administered orally and must be given parenterally 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 IV infusion, an initial bolus must be administered for full anticoagulant activity to begin.
Heparin is extensively protein bound, primarily to fibrinogen, low-density lipoproteins and globulins. 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 patients hypersensitive to it, have severe thrombocytopenia or uncontrollable bleeding (caused by something other than DIC). One author (Green 1989) states that with DIC “heparin should not be given to actively bleeding patients that have severe factor depletion and thrombocytopenia, as fatal hemorrhage may result.”
Do not administer IM, as heparin may cause hematoma formation. Hematomas, pain, and irritation may also occur after deep SQ dosing.
While heparin does not cross the placenta and is generally felt to be the anticoagulant of choice during 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 have been 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 that could 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 more information.
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 tetracyclines may partially counteract the actions of heparin.
Drug/Laboratory Interactions – Unless heparin is administered by continuous infusion, it can alter prothrombin time (PT) which can be misleading in patients also receiving a coumarin or an indandione 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 595 nm.
Heparin can cause falsely elevated values of serum thyroxine if using competitive protein binding methods of determination. Radioimmunoassay (RIA) and protein bound iodine methods are apparently unaffected by heparin.
When heparin is used as an anticoagulant in vitro (e.g., in blood collection containers), white cell counts should be performed within 2 hours of collection. Do not use heparinized blood for platelet counts, erythrocyte sedimentation rates, erythrocyte fragmentation tests, or for any tests involving complement or isoagglutinins. Errors in blood gas determinations for CO2 pressure, bicarbonate concentration or base excess may occur if heparin encompasses 10% or more of the blood sample.
Doses – Doses of heparin are controversial; dosage ranges and methods may vary widely depending on the clinician/author. Refer to the actual references for these doses for more complete information.
For adjunctive treatment of DIC: Note: Heparin therapy may be only one aspect of successful treatment of DIC. Alleviation of the precipitating cause, administration of fluids, blood, aspirin, and diligent monitoring of coagulation tests (APTT, PT), fibrin degradation products, and fibrinogen may all be important factors in the treatment of DIC.
a) 80 – 100 U/kg IV q4-6h (may be added to fluids and given as a slow drip). Low grade DIC may be treated with 25 – 40 U/kg SQ 2-3 times a day. (Byars 1987)
As adjunctive therapy in endotoxic shock:
a) 40 Units/kg IV or SQ 2-3 times a day may prevent the development of microthrombi; additional studies required to confirm positive benefits. (Semrad and Moore 1987)
Monitoring Parameters – Note: The frequency of monitoring is controversial and is dependent on several factors, including heparin dose, patient’s condition, concomitant problems, etc. Because of the high incidence of hemorrhage associated with heparin use, frequent monitoring of APTT is essential early in therapy (particularly using higher dosages) and in critically ill animals.
1) While whole blood clotting time (WBCT), partial thromboplastin time (PTT) and activated partial thromboplastin times (APTT) may all be used to monitor therapy, APTT is most often recommended.
2) Platelet counts and hematocrit (PCV) should be done periodically
3) Occult blood in stool and urine; other observations for bleeding
4) Clinical efficacy
Client Information – Because of the intense monitoring necessary with heparin’s use and the serious nature of the disease states in which it is used, this drug should be utilized only by professionals familiar with it and, preferably, in an inpatient setting.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times –
Veterinary-Approved Products: None located.
Heparin Sodium Injection 1000 U/ml, 2000 U/ml, 2500 U/ml, 5000 U/ml, 10,000 U/ml, 20,000 U/ml, 40,000 U/ml in 0.5, 1, 2, 4, 5, 10, and 30 ml amps and multi-dose vials (depending on concentration and manufacturer).
Also available for heparin sodium are pre-filled syringes in various concentrations and amounts, and premixed in normal saline and half-normal saline in 250 ml, 500 ml and 1000 ml containers.