Heparin

Absorption

Mean absolute bioavailability of enoxaparin, after 1-2 mg/kg given subcutaneously is approximately 100% in healthy volunteers. The absorption of enoxaparin is proportional to the dose, demonstrating linear absorption. The average maximum plasma anti-Xa activity is reached 3 to 5 hours after a subcutaneous injection. A 30 mg IV bolus preceding an immediate 1 mg/kg SC every twice a day led to maximum anti-Factor Xa levels of 1.16 IU/mL. Steady-state is reached within 3-4 days of treatment with a Cmax of 1.2 IU/mL. The AUC under the thrombin generation curve was 305 +/- 48.

Absorption

Almost completely absorbed after subcutaneous (sc) doses, with a bioavialability of about 87%.

Absorption

Heparin is not absorbed through the gastrointestinal tract and is therefore administered via a parenteral route. Peak plasma concentration and the onset of action are achieved immediately after intravenous administration.
Plasma heparin concentrations may be increased and activated partial thromboplastin times (aPTTs) may be more prolonged in geriatric adults (older than 60 years of age) compared with younger adults.

Absorption

Well absorbed following subcutaneous administration, with a mean bioavailability of 92% (based on anti-factor Xa activity).

Toxicity

Overdosage: hemorrhagic complications. Adverse Drug Reaction: (common) osteopenia with extended use; mild, reversible non-immunological thrombocytopenia; transient elevation of liver transaminases; alopecia. (uncommon): severe immunologically-mediated heparin-induced thrombocytopenia; anaphylactic reactions; skin rash, skin necrosis; retroperitoneal hemorrhage; angioedema

Toxicity

The oral LD50 for enoxaparin in mice is >5000 mg/kg; the subcutaneous LD50 of enoxaparin in mice is >2500 mg/kg. Accidental overdose after the administration of enoxaparin may cause hemorrhage. Enoxaparin administered by injection is mainly neutralized by gradual intravenous injection of a 1% protamine sulfate solution. The dose of protamine sulfate should be equal to the dose of enoxaparin administered: 1 mg protamine sulfate for 1 mg enoxaparin, of enoxaparin was administered in the previous 8 hours. If a minimum of 12 hours has passed since the last enoxaparin dose, protamine may not be necessary; it is important to avoid an overdose with protamine, as fatal reactions may occur.

Toxicity

In mouse, the median lethal dose is greater than 5000 mg/kg. Another side effect is heparin-induced thrombocytopenia (HIT syndrome). Platelet counts usually do not fall until between days 5 and 12 of heparin therapy. HIT is caused by an immunological reaction that makes platelets form clots within the blood vessels, thereby using up coagulation factors. It can progress to thrombotic complications such as arterial thrombosis, gangrene, stroke, myocardial infarction and disseminated intravascular coagulation. Symptoms of overdose may show excessive prolongation of aPTT or by bleeding, which may be internal or external, major or minor. Therapeutic doses of heparin give for at least 4 months have been associated with osteoporosis and spontaneous vertebral fractures. Osteoporosis may be reversible once heparin is discontinued. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100–400 mg/kg daily) of benzyl alcohol in these neonates. Its use is principally associated with the use of bacteriostatic 0.9% sodium chloride intravascular flush or endotracheal tube lavage solutions.

Toxicity

Symptoms of overdose may include excessive bleeding and bruising.

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.

Description

Heparin, the most widely used injectable blood anticoagulant, has been in the news recently because contaminated samples of raw heparin stock from China were discovered. It is one of the oldest drugs in widespread use; it was discovered in 1916 and was in medical use by the 1930s. Chemically, it is a highly sulfated polysaccharide in which the most common unit is the triply sulfated disaccharide l-iduronic acid–d-glucosamine.

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.

The Uses of Heparin

Medicine (anticoagulant), biochemical research, rodenticides.

Background

Ardeparin, marketed under the US trade name Normiflo, is a low molecular weight heparin (LMWH) anticoagulant used for the prevention of postoperative venous thrombosis. Ardeparin is derived via peroxide degradation of heparin extracted from porcine intestinal mucosa. Its molecular weight ranges from 2000 to 15,000 with an average molecular weight of 5500 to 6500. Normiflo was withdrawn from the US market in March 2000.

Background

Enoxaparin is a common low-molecular-weight heparin (LMWH) used in the prevention and management of various thromboembolic disorders. Initially approved by the FDA in 1993, it is administered by a subcutaneous or intravenous injection and marketed by several pharmaceutical companies. Enoxaparin markedly reduces the incidence of venous thromboembolism in hospitalized patients when compared to unfractionated heparin, without increasing the risk of serious bleeding.

Indications

Dalteparin is used as a prophylaxis for deep-vein thrombosis and pulmonary embolisms in patients undergoing general surgery (e.g., abdominal, gynecologic, urologic), and in patients with acute medical conditions (e.g. cancer, bed rest, heart failure, severe lung disease). It is also used in patients who have severely restricted mobility, which poses a risk for thromboembolic complications.
Dalteparin is also used concomitantly with aspirin and/or other therapy (e.g., nitrates, β-adrenergic blockers, clopidogrel, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors) to reduce the risk of acute cardiac ischemic events. The patients who undergo this treatment combination have unstable angina or non-ST-segment elevation/non-Q-wave myocardial infarction (i.e., non-ST-segment elevation acute coronary syndromes).
It is also used in the prevention of clotting during hemodialysis and hemofiltration in connection with acute renal failure or chronic renal insufficiency.

Indications

Unfractionated heparin is indicated for prophylaxis and treatment of venous thrombosis and its extension, prevention of post-operative deep venous thrombosis and pulmonary embolism and prevention of clotting in arterial and cardiac surgery. In cardiology, it is used to prevent embolisms in patients with atrial fibrillation and as an adjunct antithrombin therapy in patients with unstable angina and/or non-Q wave myocardial infarctions (i.e. non-ST elevated acute coronary artery syndrome) who are on platelet glycoprotein (IIb/IIIa) receptor inhibitors. Additionally, it is used to prevent clotting during dialysis and surgical procedures, maintain the patency of intravenous injection devices and prevent in vitro coagulation of blood transfusions and in blood samples drawn for laboratory values.

Background

Unfractionated heparin (UH) is a heterogenous preparation of anionic, sulfated glycosaminoglycan polymers with weights ranging from 3000 to 30,000 Da. It is a naturally occurring anticoagulant released from mast cells. It binds reversibly to antithrombin III (ATIII) and greatly accelerates the rate at which ATIII inactivates coagulation enzymes thrombin (factor IIa) and factor Xa. UH is different from low molecular weight heparin (LMWH) in the following ways: the average molecular weight of LMWH is about 4.5 kDa whereas it is 15 kDa for UH; UH requires continuous infusions; activated partial prothrombin time (aPTT) monitoring is required when using UH; and UH has a higher risk of bleeding and higher risk of osteoporosis in long term use. Unfractionated heparin is more specific than LMWH for thrombin. Furthermore, the effects of UH can typically be reversed by using protamine sulfate.

Indications

Enoxaparin is indicated for the prevention of ischemic complications in unstable angina and in non Q-wave myocardial infarction; it is indicated in conjunction with percutaneous intervention and/or other treatment for the management of acute ST elevation myocardial infarction.
Enoxaparin is also indicated in the prophylaxis of DVT in abdominal surgery, hip replacement, knee replacement, or medical patients with severely restricted mobility during acute illness. Additionally, enoxaparin is indicated for the inpatient treatment of DVT with or without pulmonary embolism and the treatment of outpatient DVT without pulmonary embolism.

Background

Dalteparin, a low molecular weight heparin (LMWH) prepared by nitrous acid degradation of unfractionated heparin of porcine intestinal mucosa origin, is an anticoagulant. It is composed of strongly acidic sulphated polysaccharide chains with an average molecular weight of 5000 and about 90% of the material within the range of 2000-9000. LMWHs have a more predictable response, a greater bioavailability, and a longer anti-Xa half life than unfractionated heparin. Dalteparin can also be safely used in most pregnant women. Low molecular weight heparins are less effective at inactivating factor IIa due to their shorter length compared to unfractionated heparin.

Background

Parnaparin is an heparin of low molecular weight with antithrombotic effects.

Indications

Used in the prevention and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial infarction.

Indications

For prevention of deep vein thrombosis, which may result in pulmonary embolism, following knee surgery.

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

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

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

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

This drug has an immediate onset of action. Enoxaparin increases Thrombin Time (TT) and activated partial thromboplastin time (aPTT), preventing and reducing thromboembolic complications such as DVT, pulmonary embolism, and ischemic cardiac complications. Administered at 1.5 mg/kg subcutaneously in a pharmacodynamic study, enoxaparin led to a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ±SD, 14.0±3.1) (based on areas under anti-Factor activity versus time curves) when compared to that of heparin (mean ±SD, 1.22±0.13). Increases in the TT and aPTT were 1.8 times those of the control group. Enoxaparin at 1 mg/kg subcutaneously every 12 hours led to aPTT values of 45 seconds or less in most patients. Average aPTT prolongation time on Day 1 was approximately 16% higher than on Day 4 of enoxaparin therapy.
Caution is advised during treatment with enoxaparin - the risk of hemorrhage and thrombocytopenia is increased. In pregnant women with prosthetic mechanic heart valves, the risk of thromboembolism is increased.

Pharmacokinetics

Unfractionated heparin is a highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from 3000 to 30,000 daltons. Heparin is obtained from liver, lung, mast cells, and other cells of vertebrates. Heparin is a well-known and commonly used anticoagulant which has antithrombotic properties. Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo. Small amounts of heparin in combination with antithrombin III, a heparin cofactor,) can inhibit thrombosis by inactivating Factor Xa and thrombin. Once active thrombosis has developed, larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot by inhibiting the activation of the fibrin stabilizing factor. Heparin prolongs several coagulation tests. Of all the coagulation tests, activated partial prothrombin time (aPTT) is the most clinically important value.

Pharmacokinetics

Dalteparin has an antithrombin binding site that is essential for high affinity binding to the plasma protein antithrombin (ATIII). Anti-Xa activity of plasma is used as both as an estimate of clotting activity, and as a basis to determine dosage. Its use should be avoided in patients with a creatinine clearance less than 20mL/min. In these patients, unfractionated heparin should only be used. As for monitoring, active partial thromboplastin time (aPTT) will only increase at high doses of low molecular weight heparins (LMWH). Therefore, monitoring aPTT is not recommended. However, anti-Xa activity can be measured to monitor the efficacy of the LMWH.

Pharmacokinetics

Ardeparin, an anticoagulant, is a fractionated heparin. It acts at multiple sites in the normal coagulation system to inhibit reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo.

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.

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.

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

Enoxaparin is mainly metabolized by the liver via desulfation and/or depolymerization to lower and less potent molecular weight metabolites.

Metabolism

Liver and the reticulo-endothelial system are the sites of biotransformation.

Metabolism

Not Available

Metabolism

Heparin does not undergo enzymatic degradation.

Metabolism

Liver and the reticulo-endothelial system are the sites of biotransformation. They are partially metabolized by desulphatation and depolymerization.

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]