Exam 2: Lecture X, Anticoagulants Flashcards
Hemostasis
physiological processes that prevent blood loss
major steps in hemostasis
Platelet activation
Coagulation
Fibrinolysis
major strategies in thrombosis prevention and treatment
Antiplatelet drugs
anticoagulant drugs
fibrinolytic (Thrombolytic) drugs
Platelets activated by….
TXA2, ADP, 5-HT, and fibrin
Platelets inhibited by…
PGI2 and cAMP
What regulates aggregation?
balance between PGI2 and TXA2 levels
PGI2 - is generated by vascular endothelium
TXA2 – is generated by platelets and subendothelial structures
PGI2 prevents platelet aggregation by…
- via cAMP by decreasing the release of ADP and serotonin from vesicles
TXA2 stimulates platelet aggregation by….
1) TXA2 synthesis by platelets via arachidonic acid (AA) pathway
2) 5-HT and ADP release from the granules via IP3 stimulation
Damaged endothelial and exposed collagen release…
TXA2
platelet become activated and adhere to damaged area, possibility of thrombi formation
Aspirin
- Aspirin irreversibly inactivates the cyclooxygenase
- TXA2 synthesis in platelets is reduced
- Balance between levels of PGI2 and TXA2 is altered
- Endothelial PGI2 - prevents platelet activation through the cAMP
- TXA2 production can recover only when new platelets are formed
- Typical recovery from a single dose takes 7 days
- Aspirin increases bleeding time
Clinical Use: Aspirin is the main drug related to arterial thrombosis
Dipyridamole (PERSANTINE)
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)
Ticlopidine (TICLID)
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
Clopidogrel bisulfate (PLAVIX)
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
Prasugrel (EFFIENT)
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
Abciximab (REOPRO)
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
Tirofiban (AGGRASTAT)
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
Blood coagulation involves….
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
Inhibits Factor X
Tissue factor pathway inhibitor
Inhibits Factors VIII and V
Protein C/S
inhibits thrombin II, Factors IX,X,XI and XII
Antithrombin III
Critical events in coagulation
XII -> XI -> IX -> X -> Prothrombin II -> thrombin -> I Fibrinogen -> Fibrin
Heparin MOA
Increases activity of antithrombin III - inactivates thrombin (II)
Inactivates Factors IX, X, XI, XII
metabolized in liver by heparin’s
excreted in urine
Heparin pharmacological effects
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
Heparin Therapeutic uses
Prophylaxis of thrombosis
does not cross placenta/anticoag of choice in pregnancy
heparin is ineffective in treatment of thrombi
Heparin preparations/admin
prophylactic: IV bolus, continuous infusion
Preop use: subq injection
IM inject cause painful hematomas
Partial thromboplastin time should be twice control value
Heparin Adverse effects/contraindications
- Hemorrhage - primary toxicity of heparin
- Transient, but potentially dangerous thrombocytopenia ( 5% of patients)
- Hypersensitive reactions (test dose to a patient with allergic history)
- Osteoporosis - complicate therapy
- Transient alopecia
- Contraindications:
- bacterial endocarditis / active tuberculosis
- GI ulcers
- neurosurgery /recent major surgery / recent head trauma
Protamine Sulfate
Heparin Antidote
Positively charged protein interacts with negatively charged heparin.
Forms a stable complex without anticoagulant activity.
- Antagonizes heparin effects
- Reverse anticoagulant effects of heparin after major surgery
- Originally from fish sperm or testes. Now recombinant technology
- Use minimal dose, as protamine sulfate has its own anticoagulant effect
- Given without heparin interacts with platelets and fibrinogen
- Hypersensitivity, bradycardia, and hypotension.
- Occasional anaphylactic shock in diabetic patients
LMW Heparin
Increase activity of antithrombin III - inactivate thrombin and Factor X
Advantages of LMW Heparin vs Heparin
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
Examples of LMWHeparin
Enoxaparin sodium (LOVENOX)
Dalteparin (FRAGMIN)
Ardeparin (NORMIFLO , and others )
Enoxaparin sodium (LOVENOX)
- The first approved agent for the prevention of deep vein thrombosis
- Typical use – following hip replacement surgery
- Enoxaparin for thrombolytic therapy for the treatment of acute MI
- Adverse effects: bleeding, thrombocytopenia, and local irritations
Warfarin (Coumadin) MOA
- Coumarins interfere with synthesis of clotting factors produced in liver
- Synthesis of clotting Factors II, VII, IX, and X depends upon vitamin K
- Coumarins inhibit regeneration of vitamin K:
decrease synthesis of clotting factors
Warfarin Pharmacokinetics
- Small, lipid-soluble molecules
- Well-absorbed orally
- Site of action - liver
- Peak plasma concentration in 1 hour
- 99% albumin bound (prevents diffusion into: RBC, CSF, urine, and breast milk)
- Warfarin metabolized in liver by cytochromes P450
- Warfarin undergoes enterohepatic circulation
- Excreted in urine and feces
- Have no effects upon platelets
- Onset – slow (2-3 days)
- Effective only in vivo
- Passes placenta barrier readily
Factors that increase response to oral anticoagulants
- Any cause of vitamin K deficiency
- Hyperthyroidism
- Congestive heart failure
- Old age patients
- Impaired hepatic synthesis of clotting factors
Warfarin Clinical Use
- Prophylactic treatment of venous thrombosis
- Prophylactic treatment of pulmonary embolism
- Warfarin is not used to treat arterial thrombosis disease
- Warfarin is not used in combination with streptokinase or tPA
- Warfarin can be used with heparin
Warfarin Adverse Effects
- Major bleeding in 2% of patients
- Minor bleeding in 5% of patients
- Warfarin necrosis
- patch on skin ——>gangrene
- mostly women
- 3-10 days after warfarin therapy
- thrombi in the vasculature of affected tissue
- “Purple toe” syndrome
- 3-8 weeks after warfarin therapy
- cholesterol emboli
- Subdural or intracerebral hematoma
- 10 fold higher in age >50
- Never during pregnancy: hemorrhage in fetus/abnormal bone formation
Warfarin Antidote
Vitamin K1
Other antidotes:
Fresh frozen plasma
Prothrombin complex concentrates (BEBULIN, PROPLEX T)
Recombinant factor VIIa (rFVIIa)
Vitamin K1 (Phytonadione)
- Fat soluble vitamin: K1 in plants and vitamin K2 synthesized by bacteria in GI tract
- Vitamin K1 is essential for the formation of clotting factors II, VII, IX, and X
- Vitamin K1 administered to all newborn to prevent hemorrhagic disease
- Tablets and injections (I.M., S.C). Intra-venous only for severe bleeding.
- Administered slowly to avoid hypotensive episode
- Has no effect upon anticoagulant effects of heparin
Adverse Effects: - Dizziness»_space;hypotension»_space; cyanosis»_space;anaphylaxis
- After I.V. administration deaths were reported
Hirudin
** Powerful, selective thrombin inhibitor- extracted from the saliva of medicinal leach **
- Hirudin is an anticoagulant protein (65 AA)
- Can inactivate thrombin within a clot - essentially a thrombolytic agent
- Immunologically different from heparin
- May be useful in patients, who developed allergies to heparin
- Lepirudin, (REFLUDAN) is a recombinant form of hirudin
- Lepirudin – parenterally/often antibodies develop
- Antibodies develop against thrombin-lepirudin complex
- Bivalirudin (ANGIOMAX) – parenterally/rapid onset/short half-life
Typical Schedule for Patients with MI (Beth Isreal Hospital)
Day 1 = Aspirin/heparin/warfarin/clopidogrel
Day 3 = Aspirin/warfarin/clopidogrel
Day 90 = Aspirin/Clopidogrel
1 year = aspirin
Coagulations Is a ….. process
Fast
Fibrinolysis is a …… process
slow
Tranexamic Acid (CYKLOKAPRON)
- Inhibits plasminogen activation and inhibits fibrinolysis
- Use: - bleeding after surgery,
- dental extraction,
- menorrhagia (heavy period)
- thrombolytics excess
Aminocaproic acid (AMICAR)
- Resembles aminoacid lysine
- Inhibits plasminogen interaction with fibrin via lysine binding sites
- Use: Bleeding from fibrinolytic therapy, adjunctive therapy in hemophilia
Alteplase - Adverse effects
- Hematomas
- Intracranial hemorrhage
- Gastrointestinal bleedings
- No serious allergic reactions
Alteplase Therapeutic uses/Administration
- Primary use - acute myocardial infarction
- Treatment should be initiated as soon as possible
- Heparin usually given with t-PA
Alteplase (t-PA) (ACTIVASE)
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
Urokinase Adverse effects
- Systemic bleeding
- Fever (2%-3%)
- Allergic reactions - mild/rare
Urokinase - Therapeutic uses
- Acute massive pulmonary emboli
- Patency (blockage) to intravenous catheters
- Acute coronary thrombi
Urokinase (ABBOKINASE)
Enzyme: Prepared from culture of human embryonic kidney cells
Source: Mammalian cell
Mechanism: Converts endogenous plasminogen to plasmin
Duration of action: <20 min
Anistreplase Adverse effects (5)
- Systemic bleedings
- Intracranial hemorrhage
- GI bleeding
- Hypotension
- Allergic reactions
Anistreplase (EMINASE) Therapeutic use:
- Acute myocardial infarction
2. Intracoronary thrombi
Anistreplase (EMINASE)
Inactive complex of streptokinase + human lys-plasminogen
Source: Streptococcal culture
Mechanism: Converts endogenous plasminogen to plasmin
Duration of action: 1-2 hours
Streptokinase Adverse Effects
- Systemic bleeding
- Gastrointestinal bleeding
- Hypotension
- Significant allergic potential: rashes——-> anaphylactic reactions
Streptokinase Therapeutic uses (3)
- Acute pulmonary embolism
- Acute myocardial infarction
- Arterial thrombosis
Streptokinase (STREPTASE, KABIKINASE)
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
- Complex also catalyzes degradation of fibrin plug and Factors V and VII
- Complex is inactivated by anti-streptococcal antibodies
- Loading dose is 25 mg (to overcome plasma antibodies)
- Blood viscosity decreased
- Blood pressure, total peripheral resistance and cardiac output are reduced
THROMBOLYTIC AGENTS -1
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
THROMBOLYTIC AGENTS - 2
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
Plasmin
endogenous trypsin-like enzyme digesting fibrin and lysing the clot
