Pharmacology Of Anticoagulants And Thrombolytics

Question 1

4 broad steps in hemostasis

Answer 1

Vessel injury

Vessel spasm

Platelets mass adhering to the injury site to form the plug

Formation of insoluble fibrin strands and coagulation

Question 2

2 substances that responsible for stimulating platlet aggregation

Answer 2

thromboxane A2 (TXA2)

Adenosine diphosphate (ADP)

Question 3

What is the receptor that allows platelets to attach too?

Answer 3

GP2b-3a

Question 4

3 categories of platelets aggregation inhibits

Answer 4

1) blocking the formation of TXA2
- aspirin

2) P2Y12 (ADP) receptor antagonists
- clopidogrel, prasugrel, ticagrelor

3) glycoprotein 2b-3a receptor antagonists
- Abciximab, eptifibatide, tirofiban

Question 5

P2Y12 inhibitor specifics

Clopidogrel, prasugrel, ticagrelor

Answer 5

MOA: irreversibly inhibit the P2Y12 (ADP) receptor on platelets (except for ticagrelor which is reversible)

Indicated for thrombotic events with acute coronary syndromes (unstable angina, MI, stokers etc). Is also indicated in pregnant patients

dont mix w/ omeprazolej

Question 6

GP 2b-3a receptor antagonist specifics

Abciximab, eptifibatide, tirofiban

Answer 6

MOA: block the gp2b-3a receptor for platelet aggregation
- are the most potent platelet inhibitors since they directly inhibit the platelets instead of going through pathways and are only administered through IV

Indications for patients with recent MI and stroke. Are also indicated in pregnancy

ADRs:
- can induce hemorrhages and thrombocytopenia (the chances increase with concomitant use with drugs that increase risk of bleeding such as NSAIDs and warfarin)

Question 7

High molecular weight (un fractionated) vs low molecular weight heparin

Answer 7

Both:

• negatively charged molecules found in mast cells that act to inhibit factor 10 and thrombin activation.
• bind to antithrombin via pentasaccharides and acts as an agonist for anti-thrombin 3 proteases (acts as co-factor)

HMW

• longer polymer chains
• binds to both antithrombin 3 and thrombin
• short half life
• inactivates both thrombin and factor 10a
• unpredictable responses that can cause unwanted bleeding
• may cause Heparin induce thrombocytopenia (HIT)
• less expensive

LMW

• shorter polymer chains
• binds to antithrombin 3 but not thrombin
• longer half life
• only inactivates factor 10a
• more predictable responses but still can cause unwanted bleeding
• low chance of HIT
• more expensive

Question 8

How to reverse unwanted bleeding from heparin?

Answer 8

1) Stop heparin dosages immediately

2) give protamine sulfate
- give IV 1mg:100U of heparin taken

• if HIT is present, replace protamine sulfate w/ a direct thrombin inhibitor*

Question 9

Direct thrombin inhibtitors

Argatroban, dabigatran, Pradaxa

Answer 9

MOA: inhibit the action of thrombin directly
- note: Pradaxa is used orally as a prophylaxis for stroke prevention in patients with atrial fibrillation

ADRs:

• hemorrhage
• hepatic impairment (high liver enzymes)
• fever

argatroban binds to the catalytic site of thrombin, where as lepirudin binds to both the catalytic site and the substrate recognition site

Question 10

Genetic variants for warfarin that need to be considered

Answer 10

CYP2C9 = varies active dosage

• high levels of active CYP2C9 = high dose required
• low levels of active CYP2C9 = Low dosages or dont use this

Vitamin K epoxied reductase (VKOR)
- same as above

Question 11

When to reverse warfarin and how?

Answer 11

Two possible scenarios

1) INR > 10 w/ no bleeding
- give oral vitamin K

2) Significant bleeding is present (regardless fo INR levels)
- Stop warfarin and administer Kcentra (factor 4/prothrombin complex concentrate)

Question 12

Fibrinolytics

Alteplase, tenecteplase, reteplase

Answer 12

MOA: activate plasminogen and convert it to plasmin to digest fibrin clots

• Altepase (t-PA) is a recombinant tissue plasminogen activator
• tenecteplase and reteplase are genetically engineered variants of altepase that are safer.

Indicated for life threatening clots (MI, Strokes, DVTs, pulmonary emboli) and always given IV

Question 13

Streptokinase

Answer 13

A special plasminogen activator that is produced via a B-hemolytic streptococci species
- converts plasminogen but also has worse ADRs since it is non-specific

Indicated only for STEMIs and pulmonary embolisms

can only use once since the body will develop an immune response to it (becomes anaphylactic)

Question 14

Steps in thromboxane activation of platelets

Answer 14

1) Thromboxane A2 is generated via arachidonic acid conversion
2) thromboxane A2 binds to its receptor
3) receptor activated G protein-mediated activation of phospholipase C
4) Phospholipase C hydrolyzes PIP2 -> IP3/DAG
5) IP3/DAG cause in increase in intracellular calcium concentrations
6) high calcium concentrations activate protein kinase C
7) protein kinase C activates phospholipase A2
8) phospholipase A2 activates GP2b-3a receptors
9) fibrinogen binds to GP2b-3a Which results in platelet aggregation

Question 15

What are the advantages of ticagrelor and the disadvantages of Clopidogrel?

Answer 15

Ticagrelor advantages:

• is reversible
• does not need to be in prodrug form since it does not go through 1st pass metabolism

Clopidogrel disadvantages:

• goes through first pass metabolism
• does need to be in prodrug form and is not reversible (lasts 4-9 days)

Question 16

Factor 10a inhibtors

- Rivaroxaban and Apixaban

Answer 16

MOA: directly inhibit factor 10a

Indicated for treatment and prophylaxis for DVTs

• is okay in pregnant patients but not the greatest (“c”)
• often 1st line for people who cant use heparin

Question 17

What is warfarin also known as?

Answer 17

4-hydroxycoumarin or Coumadin

Question 18

Hemostasics

• aminocaproic acid
• thrombin
• tranexamic acid

Answer 18

prevent fibrin dissolution and often used to treat or prevent excess bleeding from surgical sites