Tranexamic acid

Tranexamic acid

1. Tranexamic Acid Dr. Rupendra K Bharti MBBS MD

2. trans -4-( aminomethyl ) cyclohexanecarboxylic acid

3. Introduction It is an antifibrinolytic agent. Haemostasis necessitates balance b/w coagulation cascade that produces a fibrin clot & fibrinolytic system that dissolves a fibrin clot. Two commercially available antifibrinolytic agents are Tranexamic acid & Epsilon- Aminocaproic acid .

4. It is an synthetic derivative of amino acid lysine & acts by blocking the action of plasmin . Aprotinin another antifibrinolytic agent acts by blocking serine proteases has been withdrawn because of higher mortality. BART study

5. Pharmacodynamic properties It binds reversibly to plasminogen & prevents its interaction with fibrin . Thereby inhibiting the dissolution of fibrin clots . Plasminogen normally binds to lysine residue on fibrin & is converted to plasmin in the presence of tissue plasminogen activator (t-PA).

6. Plasmin then digests fibrin. Tranexamic acid reversibly binds to plasminogen at the lysine binding site. Preventing the binding of plasmin ( ogen ) to fibrin & the subsequent degradation of fibrin. Binding potency of it to plasminogen is 6 to 10 fold higher as compared to other antifibrinolytic drugs.

7. At blood concen . <10mg/ mL it has no effect on other blood parameters except thrombin time, even at 1 to 10mg/ mL concentration, It prolongs the thrombin time . Topical adminstration of it in CNS has caused seizures in rats.

8. Pharmacokinetic properties It is given parenterally (iv mostly), orally & topically . Effective therapeutic plasma concen . is 5 to 10mg/ mL or 10 to 15mg/ mL for inhibiting fibrinolysis . After i.m . & oral route max. Plasma concen . is obtained after 0.5 & 2-3hrs hrs respectively.

9. Bioavailability is 33% of oral drug. Not related with meals. 3% of the drug is bound to plasma proteins. Volume of distribution is 0.39L/kg & renal clearance is 8.2 L/hr. It is metabolized to small extent. It crosses placenta, B-B barrier & eye. It is excreted in urine.

10. Potential drug Interactions Thrombotic risk is increased when given along with hormonal contraceptives, factor IX, anti-inhibitor coagulant, thrombin & haemocoagulase . It may exacerbate the procoagulant effects of tretinoin in pts with ac.PML. Along with tissue plasminogen activators it may reduce efficacy of both drugs.

11. Therapeutic efficacy 1: Surgical procedures ; A: Cardiac surgery ; Cardio-Pulmonary Bypass (CPB) pts. Use of the drug significantly reduces post operative blood loss, reoperations for bleeding & transfusion requirements.

12. B: Orthopaedic surgery ; It is more efficacious in significantly reducing blood loss & transfusion requirements in total knee & hip arthroplasty . C: Spinal or Cranial surgery ; It significantly reduced transfusion requirements & perioperative blood loss. It is also efficacious in hepatic, nasal & prostatic surgery.

13. 2: Gynaecology; A; Heavy menstrual bleeding ; The drug given in a dose of 3.9-4.5gm/day for upto 5 days per cycle was shown to reduce menstrual blood loss from baseline levels. Only intrauterine delivery of levonorgesterol reduced blood loss significantly more.

14. B: Post Partum haemorrhage ; High doseage of the drug infused over 7hrs significantly reduced blood loss in PPH following vaginal delivery. WOMAN study is currently underway to assess the efficacy of drug compared with placebo in 15000 pts of PPH. Primary outcome will be incidence of death or hysterectomy need.

15. C: Uterine bleeding irregularities ; The pts treated with 250mg qid of drug for 5 days stopped bleeding within 7days in greater number then with placebos in pts using i.m . DMPA or levonorgesterel . At 4 weeks the mean bleeding-free interval was longer.

16. 3: Gastrointestinal bleeding ; The efficacy of i.v . or oral drug in upper GI bleed due to erosion or ulcer. There was reduction in mortality & was associated with lower proportions of pts requiring surgery.

17. 4: Subarachonoid haemorrhage ; In pts with SAH rebleeding occurs in 20% of survivors. Pts treated with the drug demonstrated a significant reduction in incidence of rebleeding . No beneficial effect on cerebral ischemia.

18. 5: Trauma ; Haemorrhage is a major cause of in-hospital mortality in trauma pts. CRASH-2 study The drug significantly reduced all causes of mortality at 4weeks and rate of death due to bleeding. It did not reduce the proportion of pts requiring blood product transfusion or its amount.

19. 6: Hereditary Angioneurotic oedema ; Reduction in number & severity of attacks of oedema with drug, although not all pts responded to treatment. The action is thought to involve counteracting the activation of the fibrinolytic system that is associated with functional deficiency of C1-esterase inhibitor.

20. 8: Military use ; I.M. Use in the form of autoinjector for non compressible torso haemorrhage prior to evacuation may save lives. Bleeding extremities that are amenable to pre hospital treatment with tourniquet constitutes 1/3 of all potential survivable combat injuries.

21. 7: Pts having haemophilia or on anticoagulants ; The drug given was effective in reducing bleeding after dental extraction or dental scaling. Less effect was seen in ocular surgery, sinus as well conization of cervix.

22. Pharmacoeconomic Considerations Markhov model over a lifetime horizon was used to estimate the cost effectiveness (incremental cost per life-year gained) of drug use in trauma pts with significant haemorrhage. It would be cost effective with 48$ for Tanzania, 66$ for India, 64$ for UK. 2008-2009.

23. Tolerability Well tolerated drug. Adverse Effects are : Headache, nausea, vomiting, diarrhoea, dyspepsia, dysmenorrhoea, dizziness, back pain, numbness, phosphenes & anaemia. Arthralgia , musculoskeletal pain, muscle cramps, migraine. Too rapid i.v . can cause hypotension .

24. Long term use of the drug also causes above mentioned side effects & also viral URTI, diarrhoea & insomnia in heavy menstrual bleeding. No increased risk of DVT, pulmonary embolism, cerebral thrombosis, CRAO & CRVO have been reported rarely. Not associated with increased incidence of MI, myocardial ischaemia , stroke, mortality & DVT.

25. Their have been increased incidence of post operative convulsive seizures in pts with cardiac surgery with CPB. Not associated with increased incidence of anaphylaxis or allergy .

26. Dosage & adminstration 3-4gm/day in three divided doses for upto 4 or 5 days per cycle in menorrhagia . 0.5-1gm i.v . during surgery or 0.5-2.5gm by i.v . infusion each time as required. It is Contraindicated in pts. receiving thrombin due to increased risk of thrombotic complications. Caution is required in pts. who are bedridden, renal impairment, elderly .

27. Place Of Tranexamic acid in the Treatment of Hyperfibrinolysis It is an attractive option in the prevention of excess blood loss since it inhibits fibrinolysis without apparantly affecting blood coagulation parameters to any marked extent. It is rapidly absorbed and is a reversible inhibitor with an elimination half life of 2-3 hrs It can be given parenterally , orally or topically .

28. Pharmacoeconomic analysis of the drug use in surgical pts in African countries suggest that it would save lives in countries with blood shortage. While in other it would save money by reducing overall transfusion requirements and also would cut down the risk of transmission of blood borne and viral diseases.

29. It is life saving, cost effective, used in variety of conditions, well tolerated & associated with very few severe or serious adverse effects. Thus Tranexamic acid is an effective and well tolerated antifibrinolytic agent.

30. THANK YOU