Exam 2: Lecture X, Anticoagulants

Question 1

Hemostasis

Answer 1

physiological processes that prevent blood loss

Question 2

major steps in hemostasis

Answer 2

Platelet activation
Coagulation
Fibrinolysis

Question 3

major strategies in thrombosis prevention and treatment

Answer 3

Antiplatelet drugs
anticoagulant drugs
fibrinolytic (Thrombolytic) drugs

Question 4

Platelets activated by….

Answer 4

TXA2, ADP, 5-HT, and fibrin

Question 5

Platelets inhibited by…

Answer 5

PGI2 and cAMP

Question 6

What regulates aggregation?

Answer 6

balance between PGI2 and TXA2 levels

PGI2 - is generated by vascular endothelium
TXA2 – is generated by platelets and subendothelial structures

Question 7

PGI2 prevents platelet aggregation by…

Answer 7

• via cAMP by decreasing the release of ADP and serotonin from vesicles

Question 8

TXA2 stimulates platelet aggregation by….

Answer 8

1) TXA2 synthesis by platelets via arachidonic acid (AA) pathway
2) 5-HT and ADP release from the granules via IP3 stimulation

Question 9

Damaged endothelial and exposed collagen release…

Answer 9

TXA2

platelet become activated and adhere to damaged area, possibility of thrombi formation

Question 10

Aspirin

Answer 10

1. Aspirin irreversibly inactivates the cyclooxygenase
2. TXA2 synthesis in platelets is reduced
3. Balance between levels of PGI2 and TXA2 is altered
4. Endothelial PGI2 - prevents platelet activation through the cAMP
5. TXA2 production can recover only when new platelets are formed
6. Typical recovery from a single dose takes 7 days
7. Aspirin increases bleeding time

Clinical Use: Aspirin is the main drug related to arterial thrombosis

Question 11

Dipyridamole (PERSANTINE)

Answer 11

Blocks breakdown of cAMP / cGMP in platelets by inhibiting phosphodiesterase
Increases extracellular adenosine concentrations by inhibiting adenosine uptake

Clinical Use: Alone is used rarely. A formulation with aspirin - (AGGRENOX) to prevent cerebrovascular ischemia. Dipyridamole was also used with warfarin to prevent thrombi formation in artificial heart valves, and to prevent cerebrovascular edema.

Adverse effect: Hypotension (due to vasodilation)

Question 12

Ticlopidine (TICLID)

Answer 12

Blocks ADP receptors on platelets.

Irreversibly inhibits platelet aggregation -7 day recovery

Clinical Use: Coronary artery stents. Stroke prevention
Effective in preventing transient ischemic attacks (TIAs)
Used by patients with aspirin intolerance

Adverse effect: neutropenia, thrombocytopenia & bone marrow suppression

Question 13

Clopidogrel bisulfate (PLAVIX)

Answer 13

Analog of ticlopidine

Irreversibly inhibits platelet aggregation

Clopidogrel is a prodrug activated by P450 enzyme isoform CYP2C19

Clinical Use: Coronary artery stents. Stroke prevention. Unstable angina

Adverse effect: Preferred over ticlopidine. Fewer adverse effects

Question 14

Prasugrel (EFFIENT)

Answer 14

Blocks ADP receptors on platelets

Similar to clopidogrel

Irreversibly inhibits platelet aggregation

P450 enzyme isoform CYP2C19 status have no impact upon prasugrel

Adverse effect: Increased risk of major bleeding

Question 15

Abciximab (REOPRO)

Answer 15

Directly binds to GPIIb/IIIa receptors on platelets - parenteral administered

Fab fragment of human-murine monoclonal antibody 7E3

Blocks platelet receptors for 24 hours

Clinical Use: Prevention of restenosis after coronary angioplasty

Question 16

Tirofiban (AGGRASTAT)

Answer 16

Clinical Use: Prevention of new MI

Used in combination with heparin. Given parenterally.

Oral analogs of Tirofiban were related to deaths in clinical trials

Oral analogs were abandoned

Question 17

Blood coagulation involves….

Answer 17

conversion of double fibrinogen into insoluble strand of fibrin

fibrin attaches to blood cells, “cements” the cells and forms the blood clot

fibrin is last step in complex cascade of enzymes

anticoagulants reduce formation of fibrin clots

Question 18

Inhibits Factor X

Answer 18

Tissue factor pathway inhibitor

Question 19

Inhibits Factors VIII and V

Answer 19

Protein C/S

Question 20

inhibits thrombin II, Factors IX,X,XI and XII

Answer 20

Antithrombin III

Question 21

Critical events in coagulation

Answer 21

XII -> XI -> IX -> X -> Prothrombin II -> thrombin -> I Fibrinogen -> Fibrin

Question 22

Heparin MOA

Answer 22

Increases activity of antithrombin III - inactivates thrombin (II)
Inactivates Factors IX, X, XI, XII

metabolized in liver by heparin’s
excreted in urine

Question 23

Heparin pharmacological effects

Answer 23

site of action = blood
onset = rapid

prolong clotting time
causes release of lipoprotein lipase
suppresses aldosterone secretion
increase conc of free thyroxin
slows wound healing/depresses cell mediated immunity

Question 24

Heparin Therapeutic uses

Answer 24

Prophylaxis of thrombosis
does not cross placenta/anticoag of choice in pregnancy
heparin is ineffective in treatment of thrombi

Question 25

Heparin preparations/admin

Answer 25

prophylactic: IV bolus, continuous infusion Preop use: subq injection IM inject cause painful hematomas Partial thromboplastin time should be twice control value

Question 26

Heparin Adverse effects/contraindications

Answer 26

1. Hemorrhage - primary toxicity of heparin 2. Transient, but potentially dangerous thrombocytopenia ( 5% of patients) 3. Hypersensitive reactions (test dose to a patient with allergic history) 4. Osteoporosis - complicate therapy 5. Transient alopecia 6. Contraindications: - bacterial endocarditis / active tuberculosis - GI ulcers - neurosurgery /recent major surgery / recent head trauma

Question 27

Protamine Sulfate

Answer 27

Heparin Antidote Positively charged protein interacts with negatively charged heparin. Forms a stable complex without anticoagulant activity. 1. Antagonizes heparin effects 2. Reverse anticoagulant effects of heparin after major surgery 3. Originally from fish sperm or testes. Now recombinant technology 4. Use minimal dose, as protamine sulfate has its own anticoagulant effect 5. Given without heparin interacts with platelets and fibrinogen 6. Hypersensitivity, bradycardia, and hypotension. 7. Occasional anaphylactic shock in diabetic patients

Question 28

LMW Heparin

Answer 28

Increase activity of antithrombin III - inactivate thrombin and Factor X

Question 29

Advantages of LMW Heparin vs Heparin

Answer 29

Effective as a heparin for prevention and treatment of venous thrombosis Greater bioavailability - 90% vs. 20% for heparin Longer duration of action than regular heparin Can be given less frequently – ones/day without laboratory monitoring More predictable effect Less allergic potential than heparin

Question 30

Examples of LMWHeparin

Answer 30

Enoxaparin sodium (LOVENOX) Dalteparin (FRAGMIN) Ardeparin (NORMIFLO , and others )

Question 31

Enoxaparin sodium (LOVENOX)

Answer 31

1. The first approved agent for the prevention of deep vein thrombosis 2. Typical use – following hip replacement surgery 3. Enoxaparin for thrombolytic therapy for the treatment of acute MI 4. Adverse effects: bleeding, thrombocytopenia, and local irritations

Question 32

Warfarin (Coumadin) MOA

Answer 32

1. Coumarins interfere with synthesis of clotting factors produced in liver 2. Synthesis of clotting Factors II, VII, IX, and X depends upon vitamin K 3. Coumarins inhibit regeneration of vitamin K: decrease synthesis of clotting factors

Question 33

Warfarin Pharmacokinetics

Answer 33

1. Small, lipid-soluble molecules 2. Well-absorbed orally 3. Site of action - liver 4. Peak plasma concentration in 1 hour 5. 99% albumin bound (prevents diffusion into: RBC, CSF, urine, and breast milk) 6. Warfarin metabolized in liver by cytochromes P450 7. Warfarin undergoes enterohepatic circulation 8. Excreted in urine and feces 9. Have no effects upon platelets 10. Onset – slow (2-3 days) 11. Effective only in vivo 12. Passes placenta barrier readily

Question 34

Factors that increase response to oral anticoagulants

Answer 34

1. Any cause of vitamin K deficiency 2. Hyperthyroidism 3. Congestive heart failure 4. Old age patients 5. Impaired hepatic synthesis of clotting factors

Question 35

Warfarin Clinical Use

Answer 35

1. Prophylactic treatment of venous thrombosis 2. Prophylactic treatment of pulmonary embolism 3. Warfarin is not used to treat arterial thrombosis disease 4. Warfarin is not used in combination with streptokinase or tPA 5. Warfarin can be used with heparin

Question 36

Warfarin Adverse Effects

Answer 36

1. Major bleeding in 2% of patients 2. Minor bleeding in 5% of patients 3. Warfarin necrosis - patch on skin ------>gangrene - mostly women - 3-10 days after warfarin therapy - thrombi in the vasculature of affected tissue 4. "Purple toe" syndrome - 3-8 weeks after warfarin therapy - cholesterol emboli 5. Subdural or intracerebral hematoma - 10 fold higher in age >50 6. Never during pregnancy: hemorrhage in fetus/abnormal bone formation

Question 37

Warfarin Antidote

Answer 37

Vitamin K1 Other antidotes: Fresh frozen plasma Prothrombin complex concentrates (BEBULIN, PROPLEX T) Recombinant factor VIIa (rFVIIa)

Question 38

Vitamin K1 (Phytonadione)

Answer 38

1. Fat soluble vitamin: K1 in plants and vitamin K2 synthesized by bacteria in GI tract 2. Vitamin K1 is essential for the formation of clotting factors II, VII, IX, and X 3. Vitamin K1 administered to all newborn to prevent hemorrhagic disease 4. Tablets and injections (I.M., S.C). Intra-venous only for severe bleeding. 5. Administered slowly to avoid hypotensive episode 6. Has no effect upon anticoagulant effects of heparin Adverse Effects: 1. Dizziness >>hypotension >> cyanosis >>anaphylaxis 2. After I.V. administration deaths were reported

Question 39

Hirudin

Answer 39

** Powerful, selective thrombin inhibitor- extracted from the saliva of medicinal leach ** 1. Hirudin is an anticoagulant protein (65 AA) 2. Can inactivate thrombin within a clot - essentially a thrombolytic agent 3. Immunologically different from heparin 4. May be useful in patients, who developed allergies to heparin 5. Lepirudin, (REFLUDAN) is a recombinant form of hirudin 6. Lepirudin – parenterally/often antibodies develop 7. Antibodies develop against thrombin-lepirudin complex 8. Bivalirudin (ANGIOMAX) – parenterally/rapid onset/short half-life

Question 40

Typical Schedule for Patients with MI (Beth Isreal Hospital)

Answer 40

Day 1 = Aspirin/heparin/warfarin/clopidogrel Day 3 = Aspirin/warfarin/clopidogrel Day 90 = Aspirin/Clopidogrel 1 year = aspirin

Question 41

Coagulations Is a ..... process

Answer 41

Fast

Question 42

Fibrinolysis is a ...... process

Answer 42

slow

Question 43

Tranexamic Acid (CYKLOKAPRON)

Answer 43

1. Inhibits plasminogen activation and inhibits fibrinolysis 2. Use: - bleeding after surgery, - dental extraction, - menorrhagia (heavy period) - thrombolytics excess

Question 44

Aminocaproic acid (AMICAR)

Answer 44

1. Resembles aminoacid lysine 2. Inhibits plasminogen interaction with fibrin via lysine binding sites 3. Use: Bleeding from fibrinolytic therapy, adjunctive therapy in hemophilia

Question 45

Alteplase - Adverse effects

Answer 45

1. Hematomas 2. Intracranial hemorrhage 3. Gastrointestinal bleedings 4. No serious allergic reactions

Question 46

Alteplase Therapeutic uses/Administration

Answer 46

1. Primary use - acute myocardial infarction 2. Treatment should be initiated as soon as possible 3. Heparin usually given with t-PA

Question 47

Alteplase (t-PA) (ACTIVASE)

Answer 47

Recombinant human protein - naturally occurring thrombolytic enzyme Source: Mammalian cell Mechanism: Rapidly plasminogen---> plasmin in the presence of fibrin Duration of action: 1-2 hours Binds to fibrin and activates bound plasminogen (much faster than circulating plasminogen) "Fibrin selective“ Rapidly metabolized in liver

Question 48

Urokinase Adverse effects

Answer 48

1. Systemic bleeding 2. Fever (2%-3%) 3. Allergic reactions - mild/rare

Question 49

Urokinase - Therapeutic uses

Answer 49

1. Acute massive pulmonary emboli 2. Patency (blockage) to intravenous catheters 3. Acute coronary thrombi

Question 50

Urokinase (ABBOKINASE)

Answer 50

Enzyme: Prepared from culture of human embryonic kidney cells Source: Mammalian cell Mechanism: Converts endogenous plasminogen to plasmin Duration of action: <20 min

Question 51

Anistreplase Adverse effects (5)

Answer 51

1. Systemic bleedings 2. Intracranial hemorrhage 3. GI bleeding 4. Hypotension 5. Allergic reactions

Question 52

Anistreplase (EMINASE) Therapeutic use:

Answer 52

1. Acute myocardial infarction | 2. Intracoronary thrombi

Question 53

Anistreplase (EMINASE)

Answer 53

Inactive complex of streptokinase + human lys-plasminogen Source: Streptococcal culture Mechanism: Converts endogenous plasminogen to plasmin Duration of action: 1-2 hours

Question 54

Streptokinase Adverse Effects

Answer 54

1. Systemic bleeding 2. Gastrointestinal bleeding 3. Hypotension 4. Significant allergic potential: rashes-------> anaphylactic reactions

Question 55

Streptokinase Therapeutic uses (3)

Answer 55

1. Acute pulmonary embolism 2. Acute myocardial infarction 3. Arterial thrombosis

Question 56

Streptokinase (STREPTASE, KABIKINASE)

Answer 56

Purified preparation of a bacterial protein (beta-hemolytic streptococci) Source: Streptococcal culture Mechanism: Produces activator complex that converts plasminogen to plasmin Duration of action: 20-25 min 1. Complex also catalyzes degradation of fibrin plug and Factors V and VII 2. Complex is inactivated by anti-streptococcal antibodies 3. Loading dose is 25 mg (to overcome plasma antibodies) 4. Blood viscosity decreased 5. Blood pressure, total peripheral resistance and cardiac output are reduced

Question 57

THROMBOLYTIC AGENTS -1

Answer 57

Agents are used in the emergency treatment of coronary artery thrombosis Mechanism - through the conversion of plasminogen to plasmin Ideal conditions - treatment initiated within 1-4 hours after the occlusion Major application of thrombolytic agents – coronary artery occlusion

Question 58

THROMBOLYTIC AGENTS - 2

Answer 58

Thrombolytic agents are also used for multiple pulmonary emboli and deep veins thrombosis. White thrombi – arteries Platelet-rich thrombi High blood flow rate and high shear stress of arteries Red thrombi - veins Fibrin rich + trapped red blood cells Low blood flow rate

Question 59

Plasmin

Answer 59

endogenous trypsin-like enzyme digesting fibrin and lysing the clot