Heparin

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Chapter: Essential pharmacology : Drugs Affecting Coagulation, Bleeding And Thrombosis

McLean, a medical student, discovered in 1916 that liver contains a powerful anticoagulant. Howell and Holt (1918) named it ‘heparin’ because it was obtained from liver. However, it could be used clinically only in 1937 when sufficient degree of purification was achieved.


HEPARIN

 

McLean, a medical student, discovered in 1916 that liver contains a powerful anticoagulant. Howell and Holt (1918) named it ‘heparin’ because it was obtained from liver. However, it could be used clinically only in 1937 when sufficient degree of purification was achieved.

 

Chemistry And Occurrence

 

Heparin is a nonuniform mixture of straight chain mucopolysaccharides with MW 10,000 to 20,000. It contains polymers of two sulfated disaccharide units:

 

D-glucosamine-Liduronic acid

D-glucosamine-Dglucuronic acid

 

*chain length and proportion of the two disaccharide units varies. Some glucosamine residues are N-acetylated.

 

It carries strong electronegative charges and is the strongest organic acid present in the body. It occurs in mast cells as a much bigger molecule (MW ~75,000) loosely bound to the granular protein. Thus, heparin is present in all tissues containing mast cells; richest sources are lung, liver and intestinal mucosa. Commercially it is produced from ox lung and pig intestinal mucosa.

 

Actions

 

1. Anticoagulant

 

Heparin is a powerful and instantaneously acting anticoagulant, effective both in vivo and in vitro. It acts indirectly by activating plasma antithrombin III (AT III, a serine proteinase inhibitor) and may be other similar cofactors. The heparinAT III complex then binds to clotting factors of the intrinsic and common pathways (Xa, IIa, IXa, XIa, XIIa and XIIIa) and inactivates them but not factor VIIa operative in the extrinsic pathway. At low concentrations of heparin, factor Xa mediated conversion of prothrombin to thrombin is selectively affected. The anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin (IIa) mediated conversion of fibrinogen to fibrin.

 

Low concentrations of heparin prolong aPTT without significantly prolonging PT. High concentrations prolong both. Thus, low concentrations interfere selectively with the intrinsic pathway, affecting amplification and continuation of clotting, while high concentrations affect the common pathway as well.

 

Antithrombin III is itself a substrate for the protease clotting factors; binds with the protease to form a stable complex (suicide inhibitor). However, in the absence of heparin, the two interact very slowly. Heparin enhances the action of AT III in two ways:

 

·      Long heparin molecule provides a scaffolding for the clotting factors (mainly Xa and IIa) as well as AT III to get bound and interact with each other.

·      Heparin induces conformational change in AT III to expose its interactive sites. Recently, it has been shown that a specific pentasaccharide sequence, which is present in only some of the heparin molecules, binds to AT III with high affinity to induce the conformational change needed for rapid interaction with clotting factors.

 

Inhibition of IIa requires both the mechanisms, but Xa inhibition can occur by mechanism ‘b’ alone. This probably explains why low molecular weight heparin, which is insufficient to provide a long scaffolding, selectively inhibits factor Xa.

 

Higher doses of heparin given for some time cause reduction in ATIII levels, probably a compensatory phenomenon. Sudden stoppage of conventional-dose therapy may result in rebound increase in coagulability for few days.

 

2. Antiplatelet

 

Heparin in higher doses inhibits platelet aggregation and prolongs bleeding time.

 

3. Lipaemia Clearing

 

Injection of heparin clears turbid postprandial lipaemic by releasing a lipoprotein lipase from the vessel wall and tissues, which hydrolyses triglycerides of chylomicra and very low density lipoproteins to free fatty acids; these then pass into tissues and the plasma looks clear. This action requires lower concentration of heparin than that needed for anticoagulation.

 

Facilitation of fatty acid transport may be the physiological function of heparin; but since, it is not found in circulating blood and its storage form in tissues is much less active, this seems only conjectural.

 

Pharmacokinetics

 

Heparin is a large, highly ionized molecule; therefore not absorbed orally. Injected i.v. it acts instantaneously, but after s.c. injection anticoagulant effect develops after ~60 min. Bioavailability of s.c. heparin is inconsistent. Heparin does not cross blood-brain barrier or placenta (it is the anticoagulant of choice during pregnancy). It is metabolized in liver by heparinase and fragments are excreted in urine.

 

Heparin released from mast cells is degraded by tissue macrophages—it is not a physiologically circulating anticoagulant.

 

After i.v. injection of doses < 100 U/kg, the t½ averages 1 hr. Beyond this, dosedependent inactivation is seen and t½ is prolonged to 1–4 hrs. The t½ is longer in cirrhotics and kidney failure patients, and shorter in patients with pulmonary embolism.

 

Unitage And Administration

 

Because of variable molecular size, heparin is standardized only by bioassay: 1 U is the amount of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% CaCl2 solution. Heparin sod. 1 mg has 120–140 U of activity.

 

HEPARIN SOD., BEPARINE, NUPARIN 1000 and 5000 U/ml in 5 ml vials for injection.

 

Heparin should not be mixed with penicillin, tetracyclines, hydrocortisone or NA in the same syringe or infusion bottle. Heparinized blood is not suitable for blood counts (alters the shape of RBCs and WBCs), fragility testing and complement fixation tests.

 

Dosage

 

Heparin is conventionally given i.v. in bolus doses of 5,000–10,000 U (children 50–100 U/kg) every 4– 6 hours, or the initial bolus dose is followed by continuous infusion of 750–1000 U/hr which may reduce the total dose needed and the incidence of bleeding. The dose and frequency is controlled by aPTT measurement which is kept at 50–80 sec. or 1.5–2.5 times the patient’s pretreatment value. If this test is not available, whole blood clotting time should be measured and kept at ~2 times the normal value.

 

Deep s.c. injection of 10,000–20,000 U every 8–12 hrs can be given if repeated i.v. injection or infusion is not possible. Needle used should be fine and trauma should be minimum to avoid haematoma formation. Haematomas are more common with i.m. injection—this route should not be used.

 

Low Dose (s.c.) Regimen 5000 U is injected s.c. every 8– 12 hours, started before surgery and continued for 7–10 days or till the patient starts moving about. This regimen has been found to prevent postoperative deep vein thrombosis without increasing surgical bleeding. It also does not prolong aPTT or clotting time. However, it should not be used in case of neurosurgery or when spinal anaesthesia is to be given. The patients should not be receiving aspirin or oral anticoagulants. It is ineffective in highrisk situations, e.g. hip joint or pelvic surgery.

 

Adverse Effects

 

1. Bleeding due to overdose is the most serious complication of heparin therapy. Haematuria is generally the first sign. With proper monitoring, serious bleeding is reported in 1–3% patients.

 

2. Thrombocytopenia is another common problem. Generally it is mild and transient; occurs due to aggregation of platelets. Occasionally serious thromboembolic events result. In some patients antibodies are formed to the heparinplatelet complex and marked depletion of platelets occurs— heparin should be discontinued. Even LMW heparins are not safe in such patients.

 

3. Transient and reversible alopecia is infrequent. Serum transaminase levels may rise.

 

4. Osteoporosis may develop on long-term use of relatively high doses.

 

5. Hypersensitivity reactions are rare—urticaria, rigor, fever and anaphylaxis. Patients with allergic diathesis are more liable.

 

Contraindications

 

·      Bleeding disorders, heparin induced thrombocytopenia.

·  Severe hypertension, (risk of cerebral haemorrhage), threatened abortion, piles, g.i. ulcers (risk of aggravated bleeding).

·      Subacute bacterial endocarditis (risk of embolism), large malignancies (risk of bleeding in the central necrosed area of the tumour), tuberculosis (risk of hemoptysis).

·      Ocular and neurosurgery, lumbar puncture.

·      Chronic alcoholics, cirrhosis, renal failure.

·  Aspirin and other antiplatelet drugs should be used very cautiously during heparin therapy.

 

Low Molecular Weight (LMW) Heparins

 

Heparin has been fractionated into LMW forms (MW 3000–7000) by different techniques. LMW heparins have a different anticoagulant profile; selectively inhibit factor Xa with little effect on IIa. They act only by inducing conformational change in AT III and not by bringing together AT III and thrombin. As a result, LMW heparins have smaller effect on aPTT and whole blood clotting time than unfractionated heparin (UFH) relative to antifactor Xa activity. Also, they appear to have lesser antiplatelet action—less interference with haemostasis. Thrombocytopenia is less frequent. A lower incidence of haemorrhagic complications compared to UFH has been reported in some studies, but not in others. However, major bleeding may be less frequent. The more important advantages of LMW heparins are pharmacokinetic:

 

• Better subcutaneous bioavailability (70–90%) compared to UFH (20–30%): Variability in response is minimized.

• Longer and more consistent monoexponential t½: once daily s.c. administration.

• Since aPTT/clotting times are not prolonged, laboratory monitoring is not needed; dose is calculated on body weight basis.

 

Most studies have found LMW heparins to be equally efficacious to UFH. Indications of LMW heparins are:

 

1. Prophylaxis of deep vein thrombosis and pulmonary embolism in highrisk patients undergoing surgery; stroke or other immobilized patients.

2. Treatment of established deep vein thrombosis.

3.  Unstable angina.

4. To maintain patency of cannulae and shunts in dialysis patients, and in extracorporeal circulation.

 

A number of LMW heparins have been marketed. They differ in composition, pharmacokinetics and dosage.

 

Enoxaparin: CLEXANE 20 mg (0.2 ml) and 40 mg (0.4 ml) prefilled syringes; 20–40 mg OD, s.c. (start 2 hour before surgery).

 

Reviparin: CLIVARINE 13.8 mg (eq. to 1432 anti Xa IU) in 0.25 ml prefilled syringe; 0.25 ml s.c. once daily for 510 days.

 

Nadroparin: FRAXIPARINE 3075 IU (0.3 ml) and 4100 IU (0.4 ml) inj., CARDIOPARIN 4000 anti Xa IU/0.4 ml, 6000 anti Xa IU/0.6 ml, 100, 000 anti Xa IU/10 ml inj.

 

Dalteparin: 2500 IU OD for prophylaxis; 100 U/Kg 12 hourly or 200 U/Kg 24 hourly for treatment of deep vein thrombosis. FRAGMIN 2500, 5000 IU prefilled syringes.

 

Pamparin: 0.6 ml s.c. OD for unstable angina and prophylaxis of DVT; FLUXUM 3200 IU (0.3 ml), 6400 IU (0.6 ml) inj.

 

Ardeparin: 25005000 IU OD; INDEPARIN 2500 IU, 5000 IU prefilled syringes.

 

Fondaparinux: The pentasaccharide with specific sequence that binds to AT III with high affinity to selectively inactivate factor Xa has been recently produced synthetically and given the name fondaparinux. It has been marketed in USA and some other countries.

 

Heparinoids

 

Heparan sulfate It is a heparinlike natural substance found on cell surface and intercellular matrix in many tissues. It is a less potent anticoagulant than heparin, but may have a more favourable profile of action.

 

Danaparoid is a preparation containing mainly heparan sulfate, obtained from pig gut mucosa, which is used in cases with heparin induced thrombocytopenia.

 

Lepirudin This recombinant preparation of hirudin (a polypeptide anticoagulant secreted by salivary glands of leech) acts by inhibiting thrombin directly. It is indicated in patients with heparin induced thrombocytopenia.

 

Ancrod It is an enzyme obtained from Malayan pit viper venom. It degrades fibrinogen into an unstable form of fibrin which is taken up by RE cells. Thus, fibrinogen gets depleted and an apparent heparin like effect results. It is given only by slow infusion: 2 U/kg over 6 hours for deep vein thrombosis in patients who develop thrombocytopenia or hypersensitivity reactions to heparin and require immediate anticoagulation.

 

 

Heparin Antagonist

 

Protamine sulfate

 

It is a strongly basic, low molecular weight protein obtained from the sperm of certain fish. Given i.v. it neutralises heparin weight for weight, i.e. 1 mg is needed for every 100 U of heparin. For the treatment of heparin induced bleeding, due consideration must be given to the amount of heparin that may have been degraded by the patient’s body in the mean time. However, it is needed infrequently because the action of heparin disappears by itself in a few hours, and whole blood transfusion is indicated to replenish the loss when bleeding occurs. Protamine is more commonly used when heparin action needs to be terminated rapidly, e.g. after cardiac or vascular surgery.

 

In the absence of heparin, protamine itself acts as a weak anticoagulant by interacting with platelets and fibrinogen. Being basic in nature it can release histamine in the body. Hypersensitivity reactions have occurred. Rapid i.v. injection causes flushing and breathing difficulty.

 

PROTA, PROTAMINE SULFATE 50 mg in 5 ml inj.

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