L2: Fibrinolytic, antiplatelet & drugs used in bleeding disorders

Question 1

What are types of drugs used to stop coagulation? (Anti-platlets)

Answer 1

1- Aspirin (Acetyl salicylic acid)
2- ADP receptor blockers
3- Gp IIIA/IIB receptor blockers
4- PDE inhibitors

Question 2

What is the mechanism of action of aspirin?

Answer 2

• Irreversible inhibition of COX enzyme → ↓ TXA2 → ↓ platelet aggregation.
• Irreversible acetylation of platelet cell membranes → ↓ platelet adhesions. “To collagen”
• Decrease platelet ADP synthesis → decrease platelet accumulation

Question 3

What is the duration of aspirin?

Answer 3

It lasts 7-9 days. “As it inhibits COX irreversibly, so new platelets must be formed”

“Platlets must be present in cases of surgery”

Question 4

what are the types of doses of aspirin and what does each dose cause?

Answer 4

• At higher doses (> 325 mg/day), aspirin may decrease endothelial synthesis of Prostacyclin (PGI2), which inhibits platelet activity
• Low doses (75-150 mg/day) ↓ synthesis of platelet TXA2 “in platlets” more than PGI2 in endothelial cells and avoid this effect.

Question 5

What are ADP receptor blockers?

Answer 5

Ticlopidine, Clopidogrel, Prasugrel

Question 6

What is the mechanism of action of ADP receptor blockers?

Answer 6

Irreversibly inhibit the binding of ADP to its receptor “while aspirin prevents its synthesis” on platelets → inhibit the activation of the glycoprotein IIb/IIIa receptors “common on all antiplatlets” required for platelets to bind to fibrinogen and to each other

Question 7

What is the nature of clopidogrel and what is the enzyme responsible for its biotransformation?

Answer 7

Is a prodrug → activated in the liver by CYP2C19.

Question 8

What are poor metabolizers of clopidogrel?

Answer 8

Some people have genetic deficiency in the enzymes that metabolize clopidogrel; they are called “poor metabolizers” and cannot benefit from this drug.

“Those with liver problems as well”

Question 9

What are the uses of clopidogrel?

Answer 9

❖ prophylaxis of thrombosis in both cerebrovascular and cardiovascular disease (e.g., coronary artery disease, coronary angioplasty, peripheral vascular disease, etc.).

Question 10

What are gp IIb/IIIa receptor blockers?

Answer 10

Abciximab, Eptifibatide, Tirofiban

Question 11

What is the nature of abciximab?

Answer 11

the Fab fragment of a monoclonal antibody

Question 12

What is the nature of eptifdibatide?

Answer 12

small synthetic peptide “rattle snack venom”

Question 13

What is the nature of tirofiban?

Answer 13

peptide of low MW

Question 14

What is the mechanism of action of gp IIb/IIIa receptor blockers?

Answer 14

They bind to gp IIb/IIIa and blocks binding of platelets to fibrinogen. “Prevent final stage”

Question 15

What are the uses of gp IIb/IIIa receptor blockers?

Answer 15

❖ Approved for use in patient undergoing percutaneous coronary intervention, for unstable angina, and for post-MI. “Revise the notes for these terms”

Question 16

What is the mechanism of action of PDE inhibitors?

Answer 16

Dipyridamole inhibits phosphodiesterase (PDE) enzyme → ↑cGMP → VD and inhibition of platelet activity.

Question 17

Give an example for PDE inhibitors.

Answer 17

Dipyridamole

Question 18

What are the uses of PDE inhibitors?

Answer 18

limited to pro phylaxis (combined with warfarin ) in patients with prosthetic ( mechanical) heart valves.

Question 19

What is the classification of fibrinolytics? “all IV”

Answer 19

Non-fibrin selective: Streptokinase and urokinase “bind to any plasminogen”

Fibrin selective: recombinant tissue plasminogen activator (rt-PA) “work on fibrin-bound plasminogen”

Question 20

What is the nature of streptokinase and what is its mechanism of action?

Answer 20

Streptokinase is a protein that is isolated from streptococci; it activates plasminogen into plasmin non-enzymatically.

Question 21

Is streptokinase antigenic?

Answer 21

It may be antigenic (causes allergy) in some people.

Question 22

What is the nature of urokinase and what is it prepared from now?

Answer 22

Urokinase is a protease originally isolated from urine, It is now prepared in recombinant form from cultured kidney cells.

Question 23

Which is more antigenic? streptokinase or urokinase

Answer 23

It is less antigenic than streptokinase.

Question 24

Give examples for recombinant tissue plasminogen activators “the best fibrinolytics”

Answer 24

Alteplase, Reteplase, Tenecteplase

Question 25

What differentiates recombinant tissue plasminogen activators?

Answer 25

They are most specific to fibrin-bound plasminogen

Question 26

Are recombinant tissue plasminogen activators antigenic?

Answer 26

Not antigenic or allergic

Question 27

What are the therapeutic uses of thrombolytic drugs?

Answer 27

❖ Acute myocardial infarction, ischemic stroke, pulmonary embolism, arterial thrombosis.

❖ In cases of acute MI, they should be given within 1h of onset. The maximum benefit is obtained if treatment is given within 90 minutes of the onset of pain. “The faster, the better”

❖ Before thrombolysis, care should be taken to ensure there is no liability for bleeding in a critical sit e.g., retina, CNS, etc.

Question 28

What are the adverse effects of thrombolytic drugs?

Answer 28

1) Systemic bleeding is the major adverse effect:
- The risk is high with streptokinase and low with the recent recombinant tissue plasminogen activators.

2) Streptokinase can cause allergy, fever, and hypotension during I.V. infusion. (HAF)

Question 29

What are types of coagulants and hemostatics?

Answer 29

Local agents and systemic agents

Question 30

What are the local agents for coagulation and hemostatics?

Answer 30

• Physical methods: application of pressure, cooling, or heat coagulation.
• Vasoconstrictor drugs: e.g., adrenaline nasal pack in epistaxis.
• Astringents: drugs which precipitate surface proteins e.g., Alum sulphate. “Close bleeding surface”
• Thrombin and thromboplastin: applied on the bleeding surface as powders.
• Fibrin and fibrinogen: available as dried sheets and used in surgery.

Question 31

What are the systemic agents for coagulation and hemostatics?

Answer 31

• Vitamin K: essential for synthesis of factors II, VII, IX, X by the liver.
• Fresh blood or plasma transfusion: as sources of coagulation factors.
• Plasma fractions:
  a) Thromboplastin (factor III): prepared from mammalian tissues.
  b) Antihemophilic globulin (factor VIII): given in hemophilia A.
  c) Calcium (factor IV): as a coagulation factor.
• Aminocaproic acid and Tranexamic acid: inhibitors of fibrinolytic system.

Question 32

What are the types of vitamin K?

Answer 32

1) Vitamin K1 (Phytomenadione):
- Naturally occurring fat-soluble vitamin present in green vegetables.
- It is available clinically in oral and parenteral forms.

2) Vitamin K2 is synthesized by intestinal bacteria.

Question 33

What does vitamin K dissolve in?

Answer 33

Both vitamins K1 and K2 require bile salts for absorption “as they are fat soluble” “in case of oral” from the intestine.

Question 34

What is the mechanism of action of vitamin K?

Answer 34

Vitamin K is required for posttranslational modification of clotting factors II, VII, IX, and X (1972) by liver cells.

Question 35

What are the therapeutic uses of vitamin K?

Answer 35

1) To reverse bleeding episodes caused by overdose of warfarin, and salicylates.
2) To correct vitamin deficiency caused by dietary deficiency, or in patients receiving oral antibiotics. “That kill bacteria that form vit K”
3) To prevent hypothrombinemia of the newborn: all newborns should routinely receive 1–2 mg of vitamin K directly after birth (especially in premature infants).

Question 36

What are the adverse effects of vitamin K?

Answer 36

Parenteral vitamin K1 is dissolved in oil; rapid i.v. administration can cause dyspnea, chest pain, or even death. “Must be slow”

Question 37

What is the nature of caproic acid and tranexamic acid?

Answer 37

• Aminocaproic acid is a synthetic agent that competitively inhibits plasminogen activation.
• Tranexamic acid is more potent analogue of aminocaproic acid. “Gives same response with lower dose”

Question 38

Give examples for fibrinolytic inhibitors

Answer 38

Aminocaproic acid and Tranexamic acid

Question 39

What are the uses of fibrinolytic inhibitors?

Answer 39

1) To prevent bleeding from tissues rich in plasminogen activators e.g., lung, prostatic surgery, menorrhagia, and ocular trauma.
2) Prophylaxis for rebleeding from Intracranial aneurysm
3) As adjunctive therapy in hemophilia “added to something”
4) To stop bleeding caused by toxicity of fibrinolytic drugs