A-31. Drugs used in coagulation disorders III: Fibrinolytic drugs. Drugs used in bleeding disorders Flashcards
Fibrinolytic drugs MOA
All act as plasminogen activators
Natural fibrinolytic drugs
Streptokinase (from S. hemolyticus)
Anistreplase (1:1 streptokinase and plasminogen)
Staphylokinase (from S. aureus)
Urokinase (produced by human cells)
Tissue Plasminogen Activator (tPA) (produced by human endothelium)
Recombinant fibrinolytic compounds
Alteplase, Reteplase, and Tenecteplase
Indications of fibrinolytic drugs
- ) Pulmonary emboli and DVTs- for severe cases with hemodynamic instability
- ) Ischemic stroke- ideally with 3-4.5 hours of symptom onset
- ) Acute MI- if PCI can not be performed in less than 2 hours, fibrinolytics are used
Side effects of fibrinolytic drugs
- ) Bleeding
- occurs in 15%, lethal in 0.5%; less common in shorter duration therapy
- Fibrinolytics increase PT and aPTT, as well as raise D-dimer levels as plasmin degrades fibrin clots - ) Hypersensitivity reactions - with strepto- and staphylokinase (including anistreplase)
Contraindications of fibrinolytic drugs
- Active bleeding
- Previous GI/cerebral bleeding-within 3 months
- Surgery or Trauma- including biopsies; within 10 days
- Severe Hypertension
- Aortic Dissection or Acute pericarditis
Streptokinase MOA
Binds 1:1 with plasminogen converts plasminogen to plasmin (both circulating and thrombus-related plasminogen)
Streptokinase kinetics
IV infusion with 20-40 min half-life
- Presences of anti-streptococcal Abs from previous infection requires higher starting doses
- formation of anti-streptokinase Abs after first use precludes 2nd treatment witin 6 months
Anistreplase
Advantage? Half-life?
No significant advantage over streptokinase due to in-vivo hydrolysis by fibin + blood enzymes
half life is 1.5 hour
Staphylokinase MOA
Forms 1:1 complex with plasminogen, complexed plasminogen must then be activated to plasmin by other plasminogen, then staphlokinase:plasmin complex is active
Less systemic plasminogen activation than streptokinase but fever Abs against it
Uokinase MOA, half-life, antibodies?
MOA: a serine protease which directly activates plasminogen
No antibodies against it; 15 min half-life
prourokinase and LMW urokinase have some clot selectivity
MOA of tissue plasminoen activator (tPA)
Same but with much higher affinity to fibrin-bound plasminogen more clot-selective/less systemic and is iniactived by PAI-1 in circulation
MOA of Alteplase and Reteplase
Recombinant tPA; reteplase is a deletion mutant which causes less fibrin specificity, faster action, longer half-life, more effective but inactivated by PAI-1
Tenecteplase MOA
Different tPA mutant so no PAI-1 inactivation, longer half-life, single, IV injection and more fibrin-selective
Local drugs used in bleeding disorders vasoconstrictors
Epinephrine, Norepinephrine
Local drugs used in bleeding disorders Protein-denaturing compounds
Fe(III)-chloride, K-al-sulfate, Chromoxide, Diluted H2O2
Local drugs used in bleeding disorders large surface-area molecules
Collagen, gelatin, fibrin
Systemic drugs used in bleeding disorders
A.)Vit K
B.) fibrinolytic Inhibitors-aminocaproic acid, aprotinin, amino-methylbenzoic acid, tranexamic acid
C.) Plasma fractions
D.) Desmopressin acetate
Vit K sources
Food and K2 from GI flora where both are fat soluble and require bile for absorption
MOA of Vit K
Post-translational y-carboxylation of factors II, VII, IX, X, and protein C
Effect is delayed 6 hours and fully effective at 24 hours
Kinetics of Vit K
Can be given orally or IV (IV must be slow, if rapid may cause dyspnea, chest, and back pain or death)
Indication for Vit K
- ) Reversal of oral anticoagulant- antagonize coumarin effects
- ) Newborn supplementation- due to relative lack of interstitial flora
Fibrinolytic Inhibitors
- Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid
- aprotinin
- plasma fractions
- desmopressin
Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid
MOA competitive antagonist at Lys binding site (where fibrinolytics bind) on plasminogen; orally active
Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid Indication
- ) Bleeding-fibrinolytic therapy
- ) Postsurgical bleeding-I.e. ENT, dental, urological surgeries
- ) Hemophilia- as adjunct therapy
- ) intracranial aneurysm- as prophylaxis against further bleeding
Side effects of Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid
- thrombosis
- hypotension
- myopathy
- GI upset, diarrhea, nasal congestion
Aprotinin MOA
A serine protease that inactivates plasmin, trypsin, kallikrein, and chymotrypsin
In higher concentration elastase, thrombin, and protein C as well
Aprotinin kinetics
Parenteral administration 40-100 min half-life
Aprotinin indications
- ) Bleeding due to thrombolytic treatment
2. ) Extracorporeal circulation- as in cardiac, coronary, or hepatic surgeries
Aprotinin Side effects
- ) anaphylaxis- 0.5%; small test doses given first
2. ) transaminase/creatinine evaluation- reversible
Plasma Fraction is used in
In hemophilia A and B (bleeding occurs when factor activity is <5-10% of normal)
Plasma-derived factor concentrates can be used but some risk viral transmission; plasma protein can be cryoprecipitated from whole blood
Recombinant factor concentrates are available and are of higher purity/not virally contaminated
Desmopressin (arginine vasopressin) MOA
Activation of endothelial V2 vasopressin receptors release of vWF which stabilizes factor 7 increasing its activity
Desmopressin (arginine vasopressin) indications and kinetics
Indications is mild hemophilia A or Von Willebrand disease
Kinetics can be given parenterally, orally, sublingually, or as intranasal spray
