ANTICOAGULANTS...ppt is helpful for all healthcare and departments

This ppt is helpful for all healthcare departments.

1. ANTICOAGULANTS These are drugs used to reduce the coagulability of blood 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

2. Chemistry and occurrence: MW 10,000 to 20,000. 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, intestinal mucosa. Commercially, it is produced from ox lung and pig intestinal mucosa

3. ACTIONS Anticoagulant Antiplatelet Lipaemia clearing

4. Anticoagulant The anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin ( IIa ). Low concentration of heparin prolong aPTT . High concentration prolong both i.e aPTT and PT . Low concentration interferes selectively with the intrinsic pathway affecting amplification and continuation of clotting while high concentration affect the common pathway as well.

5. Antiplatelet Heparin in higher doses inhibit platelet aggregation and prolongs bleeding time

6. Lipaemia clearing Injection of heparin clears turbid post– prandial lipemic plasma by releasing lipoprotein lipase from the vessel wall and tissues, which hydrolyses triglycerides of chylomicra and very low density lipoprotein to free fatty acids. The free fatty acids then pass into tissues and the plasma looks clear. This action requires low concentration of heparin than that needed for anticoagulation.

7. 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 over 60 minutes. Heparin does not cross blood brain barrier or placenta (it is a anticoagulant of choice during pregnancy). It is metabolised in liver by heparinase and fragmemts are excreated in urine . Heparin releases from the mast cells is degraded by the tissue macrophages , it is not a physiological circulating anticoagulant. The t1/2 is longer in cirrhotics and kidney failure patients , and shorter in patients with pulmonary embolism . However UFH is safer than LMW heparins in kidney failure patients 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

8. DOSAGE Heparin is conventionally given i.v . in a bolus dose of 5000-10000U (children 50-100U/kg) , followed by continuous infusion of 750- 1000 U/hr , the rate of infusion is controlled by aPTT measurement which is kept at 50-80 sec or 1.5-2.5 times the patient pre treatment value. Whole blood clotting time should be measured and kept at ~2 times the normal value(10-13 sec) . Hematomas are more common with i.m . injection- this route should not be used.

9. Low dose ( s.c .) regimen : 5000U of UFH 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 post operative 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 anticoagulant. This regimen is ineffective in high risk situations e.g. hip joint or pelvic surgery.

10. Adverse effects Bleeding due to overdose is the most serious complication of heparin therapy. Haematuria is generally the first sign ; other sides are GI tract , brain , joints muscles etc Heparin –induced thrombocytopenia (HIT) occurs due to aggregation of platelets Hypersenstivity reactions are rare : manifestations are urticaria , rigor , fever and anaphylaxis.

11. Contraindications Bleeding disorders , history of HIT 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 tumor ), tuberculosis (risk of haemoptysis ) Ocular and neurosurgery , lumber puncture Chronic alcoholics , cirrhosis , renal failure Aspirin and other antiplatelet drugs should be used very cautiously during heparin therapy

12. Low molecular weight (LMW) heparins Heparin has been fractionated into LMW forms (MW 3000-7000). LMW heparin have a different anticoagulant profile i.e they selectively inhibit factor Xa with little effect on thrombin. LMW heparins have smaller effect on aPTT and whole blood clotting time than UFH . They have lesser antiplatelet action. Thrombocytopenia is less frequent . The LMW Heparins are eliminated primarily by renal excretions ; are not to be used in patients with renal failure . The more important advantage of LMW heparins are Pharmacokinetics . Better subcutaneous bioavailabilty 70-90% compared to UFH (20-30 %) Since aPTT /clotting time 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 except during cardiopulmonary bypass surgery, in which high dose UFH is still the preferred anticoagulant, because LMW heparin and fondaparinux are less effective in preventing catheter thrombosis

13. Indications of LMW heparins are: Prophylaxis of deep veins thrombosis (DVT) and pulmonary embolism (PE) in high risk patients undergoing surgery; stroke or other immobilized patients. Treatment of established DVT. Unstable angina (UA) and MI. To maintain patency of cannula and shunts in dialysis patients.

14. A number of LMW heparins have been marketed. They differ in composition , pharmacokinetics and dosage e.g. Enoxaparin : CLEXANE 20 mg (0.2ml) and 40mg (0.4ml) prefilled syringes; 20 to 40 mg OD, S.C. (start 2 hr before surgery), Reviparin , Nadroparin , Dalteparin , Parnaparin , Ardeparin

15. Heparin Antagonist Protamine sulphate: It is strongly basic, low molecular weight protein obtained from the sperm of certain fish. Given i.v . it neutralises heparin mg for mg 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 patients body in the mean time. However, it is needed in frequently because action of heparin disappears by itself in few hours and whole blood transfusion is needed to replenish the loss when bleeding occurs .

16. Protamin is more commonly used when heparin action needs to be terminated rapidly e.g. after cardiac or vascular surgery. Protamin does not neutralise fondaparinux and it only partially reverses the anticoagulant effect of LMW heparin. Being basic in nature it can release histamin in the body. Hypersensitivity reactions have occurred. Protamin should be injected slowly (5 mg per min i.v .). Rapid i.v . injection causes flushing and breathing difficulty. Protamine sulfate 50 mg in 5 ml inj.