Pharmacology - Fibrinolytics powerpoint presentation

Fibrinolytics notes ppt

1. FIBRINOLYTIC DRUGS DR. KAWSALLIYA RAJ ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY

2. INTRODUCTION Drugs used to lyse thrombi/clot to recanalize occluded blood vessels (mainly coronary artery). Venous thrombi are lysed more easily by fibrinolytics than arterial Recent thrombi respond better. Fibrinolytics have little effect on thrombi > 3 days old Therapeutic rather than prophylactic Work by activating the natural fibrinolytic system

3. Fibrinolytic system

4. Fibrinolytic drugs

5. FIBRINOLYTIC DRUGS streptokinase Urokinase Prourokinase Alteplase Tenecteplase S taphylokinase Reteplase Desmoteplase Monteplase Lanoteplase Pamiteplase

6. Mechanism of action

7. Streptokinase Obtain from β haemolytic Streptococci group C Not using now because its nonfibrin specific, activates both circulating as well as fibrin bound plasminogen. Cannot be used second time due to neutralization by antibodies Plasma t½: 30–80min ADR: Highly antigenic—can cause hypersensitivity reactions ; anaphylaxis occurs in 1–2% patients Fever, hypotension and arrhythmias.

8. Urokinase E nzyme isolated from human urine C ommercially prepared from cultured human kidney cells Not in use now a days, due to availability of other better drugs

9. Alteplase (recombinant tissue plasminogen activator ( rt -P A) Recombinant DNA technology from human tissue culture Moderately specific for fibrin- bound plasminogen circulating fibrinogen is lowered only by ~ 50% rapidly cleared by liver and inactivated by plasminogen activator inhibitor-1 (PAI-1) plasma t1⁄2 is 4–8 min Often requires heparin coadministration . Nonantigenic , nausea, mild hypotension and fever may occur Expensive

10. Alteplase (recombinant tissue plasminogen activator ( rt -P A) MI: 15 mg i.v. bolus injection followed by 50 mg over 30 min, then 35 mg over the next 1 hr. (total 100 mg in 90 min) . P ulmonary embolism: 100 mg i.v. infused over 2 hr. I schaemic stroke : 0.9 mg/kg by i.v. infusion over 60 min,

11. Reteplase It is a nonglycosylated deletion mutant of rt.PA produced by recombinant technology less selective for fibrin bound plasminogen longer acting t1⁄2 of 13–16 min D ouble bolus i.v. administration of 18 mg (10U) over 2 min each 30 min apart in cases of STEMI and in PE

12. Tenecteplase Genetically engineered substitution mutant of native t-PA Higher fibrin selectivity Longer duration of action, resistance to inhibition by PAI-1 It is the only fibrinolytic agent that can be injected i.v. as a single bolus dose over 10 sec Fibrinolytic therapy can be given immediately on diagnosis of STEMI, even during transport of the patient to the hospital. Adverse effects: bleeding, anaphylaxis and arrhythmia

13. Uses of Fibrinolytics 1. Acute myocardial infarction: Major indication for fibrinolytic therapy is STEMI, alternative first line approach to emergency percutaneous coronary intervention (PCI) with stent placement. Not indicated, or may be harmful in UA and in low risk NSTEMI 2. Deep vein thrombosis (DVT): 60% DVT pts - successfully treated by fibrinolytics . Advantage is preservation of venous valves and may be a reduced risk of PE. Streptokinase, urokinase and alteplase

14. Uses of Fibrinolytics 3. Pulmonary embolism (PE): Large, life-threatening PE, where Lung function be better preserved 4. Peripheral arterial occlusion: Recanalise - 40% limb artery occlusions, those treated within 72 hr. Indicated when surgical thrombectomy is not possible. Regional intraarterial fibrinolytics - used for limb arteries with greater success. Peripheral arterial thrombolysis is followed by short-term heparin and long-term aspirin therapy. 5. Stroke : Alteplase is approved for use in ischaemic stroke within 3–4.5 hours of onset .

15. Contraindications of fibrinolytics Major trauma, head injury, surgery, ischemic stroke within 3 months Intracranial malformation or neoplasm Aortic dissection Bleeding diasthesis Pts on anticoagulants Pregnancy Uncontrolled hypertension GI bleeding

16. Antifibrinolytics Drugs which inhibit plasminogen activation and dissolution of clot. used to check fibrinolysis associated bleeding. Epsilon amino- caproic acid (EACA) and Tranexamic acid

17. Epsilon amino caproic acid (EACA): lysine-binding sites of plasminogen and plasmin —> not able to bind to fibrin and lyse it. Uses: counteract the effect of fibrinolytic drugs and bleeding due to their use. In haemophiliacs - adjunctive value for controlling bleeding due to tooth extraction, prostatectomy, trauma, etc. ADR: Hypotension, bradycardia and may be arrhythmias Ureteric obstruction, Myopathy

18. Tranexamic acid: 7 times more potent than EACA Uses: prevention/control of excessive bleeding due to: • Fibrinolytic drugs. • Cardio-pulmonary bypass surgery. • Tonsillectomy, prostatic surgery, tooth extraction in haemophiliacs Menorrhagia, especially due to IUCD. Recurrent epistaxis, hyphema due to ocular trauma, peptic ulcer ADR: nausea and diarrhoea , Thrombophlebitis of injected vein