hemostasis disorder drugs

Question 1

platelet inhibitors

Answer 1

Aspirin

ticlopidine

clopidogrel

abciximab

small mol receptor inhibitors (tirofiban, eptifibatide)

phosphodiesterase inhibitors (dipyridamole, cilostazol)

anagrelide

Question 2

aspirin (acetylsalicylic acid)

Answer 2

Inhibits the synthesis of thromboxan A2 (TxA2) by irreversible acetylation of COX-1 in platelets

• Use: reduce risk of MI and recurring transient ishcemic attacks (TIAs)
• Antithrombotic effects on platelts are seen 1-2 days after administration and lasts for the duration of the platelets life span (7-10 days)
  
  • COX is irreversibly inhibited and the platelet has no way to make more

Question 3

ticlopidine

Answer 3

ADP antagonist

• Inhibits ADP receptors on platelets which prevents activation of GPIIb-IIIa (GPIIb-IIIa promotes platelet aggregation (binds to fibrinogen))
• Inhibits platelet adhesion (I would think it would inhibit aggregation) and platelet - platelet interactions
• Use: alternative to aspirin to prevent an initial or recurrent thromboembolic stroke
• Oral
• AE: nausea, dyspnea, diarrhe (20%), hemorrhage (5%)
  
  • Rare: severe bone marrow toxicity

Question 4

clopidogrel

Answer 4

• Similar mech to ticlopidine but has a lower incidence of adverse effects
• Use: in patients with history of recent stroke/MI or established peripheral vascular disease, and in patients with stents
• Requires activation by CYP2C19 resulting in drug-drug interactions with other drugs metabolized by 2C-19 (its is better than ticlopidine if the patient is not taking other drugs)
  
  • Proton pump inhibitors
  • Anti-epileptics (diazepam, phenytoin, mephenytoin)
  • Amitryptiline, imiprimine
  • Propranolol
  • R-warfarin

Question 5

abciximab

Answer 5

• Inhibits platelet aggregation by preventing binding of fibrinogen to glycoprotein receptor IIb-IIIa on activated platelets
• Given IV to high risk patients undergoing coronary angioplasty and patients undergoing angioplasty, atherectomy and stent placement - often with clopidogrel
• Expensive
• Bleeding is most common side effect

Question 6

tirofiban and eptifibatide

Answer 6

small molecule

tiro - peptidomimetic

epti - cyclic peptide

both have short half lifes

Question 7

dipyridamole

Answer 7

phosphodiesterase inhibitors - act inside the cell

• Coronary vasodilator that also inhibits platelet aggregation
• Use: In combination with warfarin - inhibits embolism from prosthetic heart valves
  
  • In combo with aspirin, reduces thrombosis in patients with thrombotic disease

Question 8

cilostazol

Answer 8

phosphodiesterase inhibitor - acts inside the cells

• Antithrombotic, antiplastlets and vasodilatory action
• Use: intermittent claudication and PVD

Question 9

anagrelide

Answer 9

• Reduces platelet numbers directly
• Inhibits megakaryocyte development in the late postmitotic stage
• Use: treatment of thrombocytosis secondary to myeloproliferative disorders such as polycythemia vera and chronic myelogenous leukemia to reduce the risk of stroke and MI

Question 10

anticoagulants

Answer 10

calcium chelators

heparins

Question 11

calcium chelators

Answer 11

• Inhibit blood coagulation in vitro - our bodies need Ca so we can’t use it on blood that is in the body
• Examples: oxalic acid, sodium citrate, disodium edetate (EDTA)

Question 12

heparins

Answer 12

• Accelerates the action of antithrombin 3 to neutralize thrombin and other coagulation factors
• Standard heparin (UFH)
  
  • Sources: porcine intesintal mucosa and bovine lung
  • Structure: sulfated mucopolysaccharide (acidic molecule)
  • Formulations: standard, unfractionated heparin (UFH) polymer (3000-30000)
    
    • There are lots of heparins - with different weights - this is a mixture of all of them
  • Onset of action: immediate
  • Mech of action
    
    • Activates AT3 -> AT3 inactivates factor 2a and 10a

Question 13

AE of heparins

Answer 13

• Bleeding/hemorhage - minimized with carful monitoring of PTT and platelet counts
• Allergic reaction (it is an animal prodouct)
• Osteoporosis (long term therapy)
• Transient and occasionally severe heparin induced thrombocytopenia (HIT)
  
  • Type 1 = transient and rapidly reversible
    
    • Antibodies are generated against platelets
    • Results in a decrease in platelet count
  • Type 2 = severe
    
    • Antibodies decrease platelet count
    • These antibodies also activate platelets
    • This may produce a thromboembolism, which may be life threatening

Question 14

antidote for OD on standard heparin

Answer 14

• Protamine sulfate
  
  • Protamine is a basic protein that binds to heparin (anion/cation interaciton)
  • Excessive antidote must be avoided because protamine itself is an anticoagulant
    
    • Need to titrate it - just need enough so that all the heparin is bound but no more
  • Protamine is much less capable of reversing the effects of LMWH

Question 15

LMWH

Answer 15

• Advantages over UFH
  
  • Dose dependent kinetics
  • Conviencnec - can be admin subcutanous, don’t need PTT monitoring
  • Safety
• Contrainication: HIT
• Not readily reversed with protamine sulfate (no antidote)
• Monitored by anti-Xa activity assay when needed (not a good eval)

Question 16

fondaparinux

Answer 16

• Synthetic pentasaccharide anticoagulant
  
  • It is the 5 saccharides of the active site of heparin
• Unlike UHF or LMWHs it has no effect on thrombin (F2a) - it only hits Fxa
• Once daily dosing - given subcutaneously
• Uses
  
  • Venous thromboembolism prophylaxis follwing ortho surgery
  • Treatment of pulmonary embolism
  • Treatment of DVT
  • Treatment of coronary artery thromboembolism; promising but still under study

Question 17

Direct thrombin inhibitors

Answer 17

Rudins

argatroban

oral drugs(dabigatran, rivaroxaban, apixaban)

Question 18

Rudins

Answer 18

• Hirudin
  
  • 65 amino acid peptide
  • Specific thrombin inhibitor obtained from leeches
• Lepirudin - recombinant yeast derived form of hirudin
  
  • Use: anticoagulant in patients with heparin induced thrombocytopenia (HIT)
• Desirudin and bivalirudin - new recombinant hirudin analogs

Question 19

argatroban

Answer 19

• Argatroban - 2nd gen agent approved for HIT
  
  • IV
  • Cleared by the liver Unlike lepirudin - the other drug for HIT) - can be used in patients with end stage renal disease

Question 20

dabigatran etexilate (pradaxa)

Answer 20

oral drug

• First oral direct thrombin inhibitor
• Use: atrial fibrillation, DVT, PE (prophylaxis and treatment)
• Pro-drug (ester) - rapidly hudrolyzed
• Excreted in urine

Question 21

rivaroxaban (carelto)

Answer 21

oral

• Direct FXa inhibitor
• Same indications as dabigatran
• Oral - but variable bioavalibility
• Metabolized and inactivated by CYP3A4/5
• Excreted in both urine and feces

Question 22

apixaban

Answer 22

oral

• Direct FXa inhibitor
• Same indications as dabigatran and rivaroxaban
• Excreted in urine and feces

Question 23

coumarin derivatives

Answer 23

warfarin

Question 24

warfarin

Answer 24

• Interfere with hepatic synthesis of functional vitamin K dependent clotting factors
• Plasma protein binding
  
  • Extensive which accounts for:
    
    • Low volume of distribution
    • Long half life
    • Lack of urinary excretion of unchanged drug
• Metabolism
  
  • Metabolized to inactive metabolites by cytochrome P450 (CYP2C9) in liver - site of numerous drug interactions
• Target: vitamin K epoxide reductase
• Reisstance: mutations in vit K epoxide reductase - confers heritable resistance to warfarin
  
  • There is a large variation as to how people will react to this drug
• Speed of onset: slow
  
  • Several days to reach max
• Antidotes
  
  • Discontinue drug, administer large doses of vit K and FFP

Question 25

thrombolytic drugs

Answer 25

t-PA streptokinase urokinase recombinant thrombolytic agents (alteplase, reteplase, tenecteplase)

Question 26

t-PA

Answer 26

More effectors than streptokinase or anistreplase for thrombolytic therapy in MI but carries higher risk of hemorrhagic stroke

Question 27

streptokinase

Answer 27

* Non enzymatic protein produced by group C beta hemolytic streptococci * Facilitates thrombolysis through formation of activator complex whith plasminogen results in formation of plasmin * Plasmin degrades fibrin, fibrinogen and procaogulant factors 5 and 8 * Aspirin plus streptokinase may be as effective as t-PA * Hypersensitivity may occur li\>

Question 28

urokinase

Answer 28

* Parenteral thormbolytic agent (from human cultured kidney cells) * Indicated for lysis of pulmonary emboli, lysis of coronary artery thrombi associated with evolving transmural myocardial infarction * Hypersensitivity reactions occur less frequency than with streptokinase

Question 29

alteplase reteplase tenecteplase

Answer 29

* Recombinant thrombolytic agents * Alteplase * Biosynthetic recombinant form of t-PA * Considerably more expsensive than streptokinase * Not assoicated with hypersensitivity reactions * Reteplase * Recombinant plasminogen activator * Longer HL than alteplase * Tenecteplase (TNK-t-PA) * Modified human t-PA * Compared to alteplase it has a prolonged half life, increased specificity for fibrin and increased resistance to plasminogen activator inhibitor