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Pharmacology & Medical Chemistry II > Exam 2: Lecture X, Anticoagulants > Flashcards

Exam 2: Lecture X, Anticoagulants Flashcards

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1
Q

Hemostasis

A

physiological processes that prevent blood loss

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2
Q

major steps in hemostasis

A

Platelet activation
Coagulation
Fibrinolysis

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3
Q

major strategies in thrombosis prevention and treatment

A

Antiplatelet drugs
anticoagulant drugs
fibrinolytic (Thrombolytic) drugs

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4
Q

Platelets activated by….

A

TXA2, ADP, 5-HT, and fibrin

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5
Q

Platelets inhibited by…

A

PGI2 and cAMP

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6
Q

What regulates aggregation?

A

balance between PGI2 and TXA2 levels

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

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7
Q

PGI2 prevents platelet aggregation by…

A
  • via cAMP by decreasing the release of ADP and serotonin from vesicles
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8
Q

TXA2 stimulates platelet aggregation by….

A

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

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9
Q

Damaged endothelial and exposed collagen release…

A

TXA2

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

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10
Q

Aspirin

A
  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

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11
Q

Dipyridamole (PERSANTINE)

A

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)

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12
Q

Ticlopidine (TICLID)

A

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

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13
Q

Clopidogrel bisulfate (PLAVIX)

A

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

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14
Q

Prasugrel (EFFIENT)

A

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

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15
Q

Abciximab (REOPRO)

A

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

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16
Q

Tirofiban (AGGRASTAT)

A

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

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17
Q

Blood coagulation involves….

A

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

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18
Q

Inhibits Factor X

A

Tissue factor pathway inhibitor

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19
Q

Inhibits Factors VIII and V

A

Protein C/S

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20
Q

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

A

Antithrombin III

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21
Q

Critical events in coagulation

A

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

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22
Q

Heparin MOA

A

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

metabolized in liver by heparin’s
excreted in urine

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23
Q

Heparin pharmacological effects

A

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
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24
Q

Heparin Therapeutic uses

A

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

25
Q

Heparin preparations/admin

A

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

26
Q

Heparin Adverse effects/contraindications

A
  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
27
Q

Protamine Sulfate

A

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
28
Q

LMW Heparin

A

Increase activity of antithrombin III - inactivate thrombin and Factor X

29
Q

Advantages of LMW Heparin vs Heparin

A

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

30
Q

Examples of LMWHeparin

A

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

31
Q

Enoxaparin sodium (LOVENOX)

A
  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
32
Q

Warfarin (Coumadin) MOA

A
  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
33
Q

Warfarin Pharmacokinetics

A
  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
34
Q

Factors that increase response to oral anticoagulants

A
  1. Any cause of vitamin K deficiency
  2. Hyperthyroidism
  3. Congestive heart failure
  4. Old age patients
  5. Impaired hepatic synthesis of clotting factors
35
Q

Warfarin Clinical Use

A
  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
36
Q

Warfarin Adverse Effects

A
  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
37
Q

Warfarin Antidote

A

Vitamin K1

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

38
Q

Vitamin K1 (Phytonadione)

A
  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:
  7. Dizziness&raquo_space;hypotension&raquo_space; cyanosis&raquo_space;anaphylaxis
  8. After I.V. administration deaths were reported
39
Q

Hirudin

A

** 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
40
Q

Typical Schedule for Patients with MI (Beth Isreal Hospital)

A

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

41
Q

Coagulations Is a ….. process

A

Fast

42
Q

Fibrinolysis is a …… process

A

slow

43
Q

Tranexamic Acid (CYKLOKAPRON)

A
  1. Inhibits plasminogen activation and inhibits fibrinolysis
  2. Use: - bleeding after surgery,
    - dental extraction,
    - menorrhagia (heavy period)
    - thrombolytics excess
44
Q

Aminocaproic acid (AMICAR)

A
  1. Resembles aminoacid lysine
  2. Inhibits plasminogen interaction with fibrin via lysine binding sites
  3. Use: Bleeding from fibrinolytic therapy, adjunctive therapy in hemophilia
45
Q

Alteplase - Adverse effects

A
  1. Hematomas
  2. Intracranial hemorrhage
  3. Gastrointestinal bleedings
  4. No serious allergic reactions
46
Q

Alteplase Therapeutic uses/Administration

A
  1. Primary use - acute myocardial infarction
  2. Treatment should be initiated as soon as possible
  3. Heparin usually given with t-PA
47
Q

Alteplase (t-PA) (ACTIVASE)

A

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

48
Q

Urokinase Adverse effects

A
  1. Systemic bleeding
  2. Fever (2%-3%)
  3. Allergic reactions - mild/rare
49
Q

Urokinase - Therapeutic uses

A
  1. Acute massive pulmonary emboli
  2. Patency (blockage) to intravenous catheters
  3. Acute coronary thrombi
50
Q

Urokinase (ABBOKINASE)

A

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

51
Q

Anistreplase Adverse effects (5)

A
  1. Systemic bleedings
  2. Intracranial hemorrhage
  3. GI bleeding
  4. Hypotension
  5. Allergic reactions
52
Q

Anistreplase (EMINASE) Therapeutic use:

A
  1. Acute myocardial infarction

2. Intracoronary thrombi

53
Q

Anistreplase (EMINASE)

A

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

54
Q

Streptokinase Adverse Effects

A
  1. Systemic bleeding
  2. Gastrointestinal bleeding
  3. Hypotension
  4. Significant allergic potential: rashes——-> anaphylactic reactions
55
Q

Streptokinase Therapeutic uses (3)

A
  1. Acute pulmonary embolism
  2. Acute myocardial infarction
  3. Arterial thrombosis
56
Q

Streptokinase (STREPTASE, KABIKINASE)

A

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
57
Q

THROMBOLYTIC AGENTS -1

A

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

58
Q

THROMBOLYTIC AGENTS - 2

A

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

59
Q

Plasmin

A

endogenous trypsin-like enzyme digesting fibrin and lysing the clot

Pharmacology & Medical Chemistry II (43 decks)

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