Download Thrombolytic Medications

Pharmacology: Anticoagulants and Thrombolytic Drugs
INTRODUCTION:

Hemostasis: process that maintains the integrity of the circulatory systems
Primary hemostasis: platelet plug formation (platelets adhere to damaged endothelium to form plug)
Secondary hemostasis: blood coagulation (clot forms upon the conversion of fibrinogen to fibrin, and its
addition to the platelet plug)  Formation of a thrombus
o Thrombus Formation: extrinsic and intrinsic pathways merge into common pathway, leading to factor
X activation

Factor X cleaves prothrombin  thrombin

Thrombin cleaves fibronigen  fibrin

Fibrin incorporated into thrombus

Thrombolysis/Fibronolysis: process of fibrin digestion by plasmin (protease)
In response to injury, endothelial cells synthesize and release tissue plasminogen activator (t-PA)
t-PA converts plasminogen  plasmin
Plasmin cleaves fibrin and dissolves the clot
Endogenous Inhibitors of this Process:
o PAI-1/PAI-2: inhibit t-PA
o α2-antiplasmin: inhibitor of plasmin
COAGULATION DISORDERS:

3 Major Classes of Anticoagulant Drugs:
Indirect Thrombin Inhibitors: Heparin, Fodaparinux
Parenteral Direct Thrombin Inhibitors: Hirudin, Bivalirudin, Argatroban
Oral Anticoagulants: Warfarin, next generation drugs (Apixaban, Pradaxa, Rivaroxaban)

Indirect Thrombin Activators:
General MOA: antithrombotic effect due to interaction with antithrombin III (ATIII) and factor Xa
Preparations:
o Unfractionated heparin
o Low-molecular weight heparin
o Fondaparinux (synthetic polysaccharide)
Heparin:
o General: heterogeneous mixture of sulfated mucopolysaccharides
o Heparin Targets:

Thrombin

Factor Xa

Factor IXa
o MOA: activated ATIII binds heparin and efficiently degrades thrombin and factor X
o Therapeutic Use:

Venous thrombosis (initial treatment)

Pulmonary embolism (initial treatment)

Acute MI (initial treatment)

Surgery requiring cardiopulmonary bypass

Patients with DIC

Unstable angina
o Pharmacokinetics: LMW heparin preparations have more predictable pharmacokinetics than HMW
heparin

LMW can be given subQ and without laboratory monitoring
o Management of Heparin Treatment:

Full-dose heparin therapy by continuous IV infusion needs to be monitored by activated
partial thromboplastin time (aPTT)

Can give subQ heparin for long-term anticoagulant therapy in patients with contraindications
for warfarin use (ie. pregnancy)
o Toxicity:

Bleeding: incidence somewhat less in patients treated with LMW form
 Protamine Sulfate: can be given in cases of life-threatening hemorrhage to reverse
the effects of heparin (binds tightly and neutralizes it)

Heparin-induced thrombocytopenia: decreased platelet count; lower incidence with LMW
form
-


Fondaparinux:
o Use: approved for thromboprophylaxis of patients undergoing hip or knee surgery

To prevent pulmonary embolism and deep vein thrombosis
o Management: similar to LMW heparin

Can be used with daily subQ administration

Does not require monitoring
Parenteral Direct Thrombin Inhibitors:
Drugs in this Class:
o Hirduin: bivalent specific, irreversible thrombin inhibitor (leech saliva)
o Bivalirudin: bivalent inhibitor of thrombin
o Argatroban: small molecule thrombin inhibitor
Drug Targets:
o Thrombin
Therapeutic Use/Management:
o Hirudin:

Treatment of patients with heparin-induced thrombocytopenia

Administered by IV

Dos adjusted to maintain aPTT at 1.5-2
o Bivalirudin:

Alternative to heparin in patients undergoing coronary angioplasty

Administered by IV
o Argatroban:

Alternative to hirudin for prophylaxis treatment of patients with or at risk of developing
heparin-induced thrombocytopenia
Toxicity:
o Use with caution in renal failure: can accumulate and cause bleeding
o Development of anti-hirudin Abs: can cause paradoxical increase in aPTT (daily monitoring of aPTT
recommended)
Oral Direct Thrombin Inhibitors:
Warfarin:
o General: synthetic derivative of coumarin
o Pharmacokinetics:

Administered as a sodium salt

Has 100% bioavailability

Long T½ in plasma (36 hours)

Slower acting than heparin (for long term management, NOT for an acute event)
o MOA: inhibits the vitamin-K dependent synthesis of biologically active forms of the Ca++-dependent
clotting factors (prothrombin, VII, IX, X) and protein C (regulatory factor)

Blocks gamma-carboxylation of glutamate residues in coagulation factors
o Therapeutic Use:

Prevent progression or recurrence of acute DVTs or pulmonary embolism (follows initial
course of heparin)

Prevention of venous thromboembolism in patients undergoing orthopedic or gynecological
surgery

Preventing systemic emboli in patients with:
 Acute MI
 Prosthetic heart valves
 Chronic atrial fibrillation
o Management:

International Normalized Ration (INR): therapeutic range for oral anticoagulant therapy
 Defined as patient prothombin time/mean of normal prothrombin time for the lab
 Prothrombin time determined from a fasting blood sample obtained 8-14 hours
after the last dose of an oral anticoagulant
o Toxicity/DDIs:

Use with caution:
 Patients with congenital coagulation deficiency
 Patients with thrombocytopenia
 Patients with hepatic or renal insufficiency

-
Never use:
 Patients who are pregnant (readily crosses the placenta and causes hemorrhagic
disorder in the fetus/serious birth defects)

Warfarin resistance: can develop in some patients (most common in those with advanced
cancer); progression/recurrence of the thrombotic event
 Difficult to manage because raising INR in these patients also increases risk of
bleeding

DDIs:
 Decrease anticoagulant effect: barbiturates and rifampin
 Increased anticoagulant effect: aspirin and cephalosporins
New Drugs: main advantage to these new ones is that they do not require drug monitoring
o Pradaxa: targets thrombin only (already FDA approved)
o Rivaroxiban: targets factor Xa
o Apixaban: targets factor Xa
THROMBOSIS:

Fibrinolytic Drugs:
General MOA: cause rapid lysis of thrombi by catalyzing the activation of plasmin
Tissue Plasminogen Activator (tPA):
o General: endogenous serine protease that is a poor plasminogen activator in the absence of fibrin
o MOA: binds to fibrin via lysine binding sites at amino terminus and activates bound plasminogen

Presence of fibrin increases the speed of activation several hundredfold
o Clearance: occurs by hepatic metabolism

Half Life: 5-10 minutes
o Use: lyses thrombi during the treatment of

Acute MI

Pulmonary emobolism

Severe DVT
o Recombinant tPA: Reteplase and Tenecteplase

Increased half lives (allow for convenient bolus dosing)
Streptokinase:
o General: produced by beta-hemolytic streptococci
o MOA: no intrinsic enzymatic activity, but forms a stable complex with plasminogen, producing a
conformational change that exposes the active site on plasminogen  plasmin
o Use: decreased due to advent of newer agents
Recent Studies: suggest that angioplasty without stent placement is superior to thrombolytic therapy, when it is
feasible
Toxicity:
o Hemorrhage: major toxicity of all thrombolytic agents; results from 2 factors

Lysis of fibrin in physiological thrombi at sites of vascular injury

A systemic lytic state that results from systemic formation of plasmin, causing
 Fibrinogenolysis
 Destruction of other coagulation factors (V and VIII especially)

Aminocaproic acid: potent inhibitor of fibrinolysis (blocks interaction of fibrin and plasmi)
and can reverse excessive fibrinolysis
Contraindications to Thrombolytic Therapy:
o Any of the following within 10 days:

Surgery (including organ biopsy)

Puncture of noncompressible vessels

Serious trauma

Cardiopulmonary resuscitation
o Within 3 months: serious GI bleeding
o History of HTN (diastolic >110 mmHg)
o Active bleeding or hemorrhagic disorder
o Previous cerebrovascular accident or active intracranial process
o Aortic dissection
o Acute pericarditis

Antiplatelet Drugs:
Aspirin:
o MOA: blocks platelet aggregation and vasoconstriction by inhibiting synthesis of thromboxane A2

Acetylates a serine residue near the active site of COX-1 (responsible for production of
precursor of TXA2)

Effects last for the life of the platelet (7-10 days)
o Use:

Low dose immediately after a heart attack to reduce the risk of another or to prevent the
death of cardiac tissue

Low dose long-term for prevention of:
 Heart attacks
 Strokes
 Blood clot formation
o Toxicity:

Increased at higher doses (especially bleeding)

Use in combination with clopidogrel or warfarin increases risk of upper GI bleeding
Dipyridamole:
o MOA: vasodilator
o Use: only recommended for postoperative prophylaxis of thromboemboli in patients with prosthetic
heart valves, in combination with warfarin
o Toxicity:

N/V/D most common

Leukopenia is most severe
Clopidogrel (Plavix):
o MOA: platelet ADP receptor antagonist (inhibits platelet activation)
o Use:

Used with aspiring after angioplasty (continued for at least 1 year)

Reduce stroke and MI in patients with recent strokes and MIs

Treatment of peripheral arterial disease

Treatment of acute coronary syndrome
o Toxicity: more favorable side effect profile that dipyridamole and ticlopidine

Less frequent cases of thrombocytopenia and leukopenia
Ticlopidine:
o MOA: platelet ADP receptor antagonist (inhibits platelet activation)
o Use:

Reduce the risk of thrombotic stroke in patients who have experience stroke precursors
and/or in patients who have had a completed thrombotic stroke
o Toxicity:

N/V/D most common

Leukopenia is most severe
Glycoprotein IIb/IIIa Inhibitors: inhibit platelet aggregation by blocking the binding of these platelet-surface
integrins to fibrinogen and von Willebrand factor (block cross-linking of platelets)
o Abciximab:

MOA: Fab fragment of a humanized mAb against the AlphaIIbBeta3 receptor

Use:
 In conjunction with percutaneous angioplasty for coronary thromboses
 Use along with aspirin and heparin effective in preventing restonsis, recurrent MI
and death

Toxicity: major side effect is bleeding
 If severe: platelet transfusions can reverse aggregation defect
o Eptifibatide:

MOA: cyclic peptide inhibitor of the fibrongen binding site on AlphaIIbBeta3 integrin

Use:
 Treatment of acute coronary syndrome (IV)
 Angioplastic coronary interventions (IV)- have reduced MI and death by ~20%

Toxicity: major side effect is bleeding
 If severe: platelet transfusions can reverse aggregation defect
o



Tirofiban:

MOA: nonpeptide, small-molecule inhibitor of AlphaIIbBeta3 integrin

Use: in conjunction with heparin
 Non-Q wave MI
 Unstable angina

Toxicity: bleeding on local sites of clinical intervention and systemically
 Major bleeding possible
 Transfusions required to terminate bleeding
EXAMPLE OF TREATMENT REGIMEN FOR ACUTE MI:
Prehospital:
o Aspirin
o Oxygen (CPR if necessary)
o Analgesia/ECG/Antiarryhtmics
o Defibrillation
Hospital:
o Antiarrhythmics an same supportive care as above
o Fibrinolytic therapy (up to 12 hours after onset), OR
o Coronary angioplasty, OR
o Coronary artery bypass graft surgery
o Anticoagulant (aspirin, heparin, start on warfarin)
Outpatient:
o Antiarrhythmics as necessary
o Anticoagulant (aspirin or warfarin)
o Antiplatelet drug