A-31. Drugs used in coagulation disorders III: Fibrinolytic drugs. Drugs used in bleeding disorders

Question 1

Fibrinolytic drugs MOA

Answer 1

All act as plasminogen activators

Question 2

Natural fibrinolytic drugs

Answer 2

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)

Question 3

Recombinant fibrinolytic compounds

Answer 3

Alteplase, Reteplase, and Tenecteplase

Question 4

Indications of fibrinolytic drugs

Answer 4

1. ) Pulmonary emboli and DVTs- for severe cases with hemodynamic instability
2. ) Ischemic stroke- ideally with 3-4.5 hours of symptom onset
3. ) Acute MI- if PCI can not be performed in less than 2 hours, fibrinolytics are used

Question 5

Side effects of fibrinolytic drugs

Answer 5

1. ) 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
2. ) Hypersensitivity reactions - with strepto- and staphylokinase (including anistreplase)

Question 6

Contraindications of fibrinolytic drugs

Answer 6

• Active bleeding
• Previous GI/cerebral bleeding-within 3 months
• Surgery or Trauma- including biopsies; within 10 days
• Severe Hypertension
• Aortic Dissection or Acute pericarditis

Question 7

Streptokinase MOA

Answer 7

Binds 1:1 with plasminogen converts plasminogen to plasmin (both circulating and thrombus-related plasminogen)

Question 8

Streptokinase kinetics

Answer 8

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

Question 9

Anistreplase

Advantage? Half-life?

Answer 9

No significant advantage over streptokinase due to in-vivo hydrolysis by fibin + blood enzymes
half life is 1.5 hour

Question 10

Staphylokinase MOA

Answer 10

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

Question 11

Uokinase MOA, half-life, antibodies?

Answer 11

MOA: a serine protease which directly activates plasminogen
No antibodies against it; 15 min half-life
prourokinase and LMW urokinase have some clot selectivity

Question 12

MOA of tissue plasminoen activator (tPA)

Answer 12

Same but with much higher affinity to fibrin-bound plasminogen more clot-selective/less systemic and is iniactived by PAI-1 in circulation

Question 13

MOA of Alteplase and Reteplase

Answer 13

Recombinant tPA; reteplase is a deletion mutant which causes less fibrin specificity, faster action, longer half-life, more effective but inactivated by PAI-1

Question 14

Tenecteplase MOA

Answer 14

Different tPA mutant so no PAI-1 inactivation, longer half-life, single, IV injection and more fibrin-selective

Question 15

Local drugs used in bleeding disorders vasoconstrictors

Answer 15

Epinephrine, Norepinephrine

Question 16

Local drugs used in bleeding disorders Protein-denaturing compounds

Answer 16

Fe(III)-chloride, K-al-sulfate, Chromoxide, Diluted H2O2

Question 17

Local drugs used in bleeding disorders large surface-area molecules

Answer 17

Collagen, gelatin, fibrin

Question 18

Systemic drugs used in bleeding disorders

Answer 18

A.)Vit K
B.) fibrinolytic Inhibitors-aminocaproic acid, aprotinin, amino-methylbenzoic acid, tranexamic acid
C.) Plasma fractions
D.) Desmopressin acetate

Question 19

Vit K sources

Answer 19

Food and K2 from GI flora where both are fat soluble and require bile for absorption

Question 20

MOA of Vit K

Answer 20

Post-translational y-carboxylation of factors II, VII, IX, X, and protein C
Effect is delayed 6 hours and fully effective at 24 hours

Question 21

Kinetics of Vit K

Answer 21

Can be given orally or IV (IV must be slow, if rapid may cause dyspnea, chest, and back pain or death)

Question 22

Indication for Vit K

Answer 22

1. ) Reversal of oral anticoagulant- antagonize coumarin effects
2. ) Newborn supplementation- due to relative lack of interstitial flora

Question 23

Fibrinolytic Inhibitors

Answer 23

• Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid
• aprotinin
• plasma fractions
• desmopressin

Question 24

Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid

Answer 24

MOA competitive antagonist at Lys binding site (where fibrinolytics bind) on plasminogen; orally active

Question 25

Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid Indication

Answer 25

1. ) Bleeding-fibrinolytic therapy
2. ) Postsurgical bleeding-I.e. ENT, dental, urological surgeries
3. ) Hemophilia- as adjunct therapy
4. ) intracranial aneurysm- as prophylaxis against further bleeding

Question 26

Side effects of Aminocaproic acid, p-amino-methylbenzoic acid, and tranexamic acid

Answer 26

• thrombosis
• hypotension
• myopathy
• GI upset, diarrhea, nasal congestion

Question 27

Aprotinin MOA

Answer 27

A serine protease that inactivates plasmin, trypsin, kallikrein, and chymotrypsin
In higher concentration elastase, thrombin, and protein C as well

Question 28

Aprotinin kinetics

Answer 28

Parenteral administration 40-100 min half-life

Question 29

Aprotinin indications

Answer 29

1. ) Bleeding due to thrombolytic treatment

2. ) Extracorporeal circulation- as in cardiac, coronary, or hepatic surgeries

Question 30

Aprotinin Side effects

Answer 30

1. ) anaphylaxis- 0.5%; small test doses given first

2. ) transaminase/creatinine evaluation- reversible

Question 31

Plasma Fraction is used in

Answer 31

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

Question 32

Desmopressin (arginine vasopressin) MOA

Answer 32

Activation of endothelial V2 vasopressin receptors release of vWF which stabilizes factor 7 increasing its activity

Question 33

Desmopressin (arginine vasopressin) indications and kinetics

Answer 33

Indications is mild hemophilia A or Von Willebrand disease

Kinetics can be given parenterally, orally, sublingually, or as intranasal spray