PPM2 Anticoagulant and Thrombolytic Drugs

Required Readings:

Brenner          Chp. 16:  “Anticoagulant, Antiplatelet, and Fibrinolytic Drugs”

CMDT 2003    Chp. 9:  “Pulmonary Thromboembolism; Treatment;

                                    A. Anticoagulation,” pp. 285-288.

                        Chp. 10:  “Acute Myocardial Infarction; Treatment;

                                    B.  Thrombolytic Therapy,” pp. 350-353.

Objectives:

1.         Review the process of normal hemostasis; distinguish between thrombosis and embolism.

Tim, Brenner pg160

Normal hemostasis:  

1. blood vessel injury

2. hemorrhage prevention by vasospasm

3. reduction of bleeding and blood flow

4. facilitation of platelet adhesion and coagulation

5. blood exposed to extravascular collagen

6. adherence of platelets to injured vessel wall

7. initiation of sequential activation of clotting factors

            a. intrinsic pathway is activated by surface contact w/ a foreign body or extravascular tissue

            b. extrinsic pathway is activated by a complex tissue factor

            c. pathways converge (common pathway) w/ the activation of factor X, which is the major rate limiting step in the coagulation cascade

8. activation of factor X leads to formation of thrombin

9. thrombin catalyzes the conversion of fibrinogen to fibrin

10. fibrin meshwork traps erythrocytes and platelets completing the formation of a hemostatic thrombus (clot)

Thrombosis: formation of a clot that is stationary in an artery or vein.

            Arterial thrombosis (white thrombi)- atherosclerosis and other abnormalities affecting the vascular epithelium may serve as a stimulus for platelet aggregation and blood coagulation in arteries.

            Venous thrombosis (red thrombi)- pooling, sluggish blood flow, and inflammation of veins that permits inappropriate platelet adhesion and coagulation in vessels.

            Platelet aggregation precedes coagulation in both arteries and veins most commonly, venous thrombi has a lesser degree of platelet aggregation and greater degree of more direct coagulation in certain instances (pooling).

Embolism: a thrombus that becomes dislodged from a vessel wall and travels through the circulation is an embolus which eventually occludes a smaller vessel that may be in the lungs or brain, thereby causing pulmonary embolism or a cerebrovascular accident.

Kate Brenner 160

When a normal blood vessel is injured, hemorrhage is prevented by vasospasm, formation of platelet plug, and the formation of a fibrin clot.  After the vessel is repaired, the clot is removed via process of fibrinolysis.  Vasospasm reduces bleeding and blood flow and thereby facilitates platelet adhesion and coagulation.  Exposure of the blood to extravascular collagen causes adherence of platelets to the injured vessel wall and initiates the sequential activation of numerous coagulation factors.  

The intrinsic pathway may be activated by surface contact with a foreign body, whereas the extrinsic pathway is activated by tissue factor.  The pathways converge with the activation of factor X, the major rate-limiting step in the cascade, which leads to the formation of thrombin which catalyzes the conversion of fibrinogen into fibrin.  The fibrin meshwork traps erythrocytes and platelets to complete the formation of a hemostatic thrombus (clot).

Thrombosis: the process of inappropriate (often due to atherosclerosis and other abnormalities affecting vascular endothelium) platelet aggregation and coagulation forming clots in arteries and veins.   

Embolism: an arterial or venous thrombus may become dislodged from the vessel wall and travel through the circulation and eventually occludes a smaller vessel in the lungs or brain, thereby causing a PE or a cerebrovascular accident, respectively.

Anonymous Brenner p160

• Normal Hemostasis: See fig 16-1

1)      When a small blood vessel is injured, vasospasm reduces blood flow and facilitates platelet aggregation and coagulation.

2)      The platelets adhere to extravascular collagen and are activated to release mediators that cause platelet aggregation and the formation of a platelet plug to arrest bleeding.

3)      Exposure of the blood to tissue factors also activates coagulation and leads to the formation of a fibrin clot, which arrests bleeding until the vessel is repaired.

4)      After the vessel is repaired, the clot is removed by the process of fibrinolysis.

• Thrombosis: Atherosclerosis and other abnormalities cause vascular damage and trigger platelet aggregation, and then inappropriate platelet adhesion and coagulation. They stick to the walls and cause blockages.

• Embolism: arterial or venous thrombi that break loose and travel through the circulation and eventually occludes a smaller vessel in the lungs or brain, thereby causing pulmonary embolism or a CVA.

Anonymous   Brenner pg. 160-1

1) When a small blood vessel is injured, vasospasm reduces blood flow and facilitates platelet aggregation and coagulation.

2) The platelets adhere to extravascular collagen and are activated to release mediators that cause platelet aggregation and the formation of a platelet plug to arrest bleeding.

3) Exposure of the blood to tissue factors also activates coagulation and leads to the formation of a fibrin clot, which arrests bleeding until the vessel is repaired.

4)  After the vessel is repaired, the clot is removed by the process of fibrinolysis.

Thrombosis vs. Emoblism:

Atherosclerosis and other abnormalities affecting the vascular endothelium may serve as a stimulus for platelet aggregation and blood coagulation in arteries.  Venous pooling, sluggish blood flow and inflammation of veins may permit inappropriate platelet adhesion and coagulation in vessels.  These form thrombus (or clots) in the vessels that adhere to the wall of the vessel.  An arterial or venous thrombus may become dislodged from the vessel wall so as to form an embolus that travels through the circulation and eventually occludes a smaller vessel in the lungs or brain.

Anonymous p. 160

Normal Hemostasis:

Hemorrhage is prevented in a small blood vessel injury by vasospasm, formation of a platelet plug, and formation of a fibrin clot. After the vessel is repaired the clot is removed via fibrinolysis. Factor X is the major rate-limiting step in the coagulation cascade. Factor X activation leads to formation of thrombin. Thrombin catalyzes conversion of fibrinogen to fibrin. The fibrin meshwork traps erythrocytes & platelets to complete formation of a hemostatic thrombus (clot).

Fig 16.1 Normal Hemostasis

Table 16.1 Coagulation Factors

Fig 16.2 Blood Coagulation & sites of Drug Action

Thrombosis: Platelet aggregation & blood coagulation in arteries/veins.

Embolus: Any thing such as a thrombus, air, a piece of catheter, or fat that occludes a smaller vessel and prevents circulation and oxygenation to the area beyond.

In the Lungs  = Pulmonary Embolism.

In the Brain  = Cerebrovascular Accident.

2.         Briefly state the mechanism of action of oral anticoagulants and the time frame necessary for onset of action.  (representative drug: warfarin)

Tim, Brenner pg 160-161

Mechanism of action: Warfarin retards the coagulation and prevents the occurance or enlargement of a thrombus by mimicking vitamin K which inhibits the synthesis of clotting factors II, VII, IX, and X whose carboxylation is dependent on a reduced form of vitamin K.

Onset of action: The maximal effect of oral anticoagulants is not observed until 3-5 days after starting tx.

Kate Brenner 161

Warfarin and other oral anticoagulants are structurally related to vitamin K.  These drugs work by inhibiting the synthesis of clotting factors II (prothrombin), VII, IX, and X, whose carboxylation is dependent on a reduced form of vit.k.  Warfarin blocks the reduction of oxidized Vit.k.,  and thereby prevents the posttranscriptional carboxylation of these four factors.  Oral anticoagulants also work by inhibiting the synthesis of proteins C and S(also dependent of Vit.K), which are endogenous anticoagulants that inactivate factors V and VIII and promote fibrinolysis.  It is possible that the inhibition of proteins C and S contributes to a transient procoagulant effect of the oral anticoagulants when they are first administered.  The oral anticoagulants have a delayed onset of action, owing to the time required to deplete the pool of circulating clotting factors after synthesis of new factors is inhibited. The half-life of circulating factors ranges from 6-50 hrs.  Therefore, the maximal effect of oral anticoagulants is not observed until 3-5 days after starting therapy.  Pts with acute thromboembolism are usually treated with heparin and an oral anticoagulant, and the heparin may be withdrawn after the oral anticoagulant becomes effective.

Anonymous Brenner p160-162

• Mech. Of Action:

• Anticoagulants are drugs that retard coagulation and thereby prevent the occurrence or enlargement of a thrombus.

• Warfin and other oral anticoagulants are structurally related to vitamin K. These drugs work by inhibiting the synthesis of clotting factors II (prothrombin), VII, IX and X, whose carboxylation is dependent on a reduced form of vitamin K. Warfin, blocks the reduction of oxidized vitamin K and thereby prevents the posttranscriptional carboxylation of these four factors.

• Oral anticoagulants also work by inhibiting the synthesis of proteins C and S, which are endogenous anticoagulants that inactivate factors V and VII and promotes fibrinolysis.

• Time Frame:

o       Oral anticoagulants have a delayed onset of action. The maximal effect time is not observed until 3-5 days after starting therapy.

• Bioavailability:

o       Warfin is completely absorbed after oral ingestion, and 99% of the drug is bound to plasma proteins and it is almost completely metabolized by two cytochrome P450 enzymes. These excellent properties make warfin the oral anticoagulants of choice for pts requiring long term therapy, for DVT, AFib or have an artificial heart valve.

Anonymous   Brenner p. 161

MOA: Warfarin blocks the reduction of oxidized vitamin K and thereby prevents the posttranscriptional carboxylation of clotting factors II, VII, IX, and X.  Oral anticoagulants also work by inhibiting the synthesis of proteins C and S, which are endogenous anticoagulants that inactivate factors V and VIII and promote fibrinolysis.  

Time frame necessary for onset of action: Oral anticoagulants have a delayed onset of action.  The half-life of circulating factors II, VII, IX, and X ranges from 6 hours (factor VII) to 50 hours (factor II).  Therefore, the maximal effect of oral anticoagulants is not observed until 3-5 days.

Anonymous p. 160 – 162

MOA:

Retardation of coagulation

Prevention of enlargement of a thrombus

Structurally related to Vitamin K

Inhibiting vitamin K-dependent synthesis of clotting factors II (Prothrombin) VII, IX, & X

Inhibiting synthesis of proteins C & S (endogenous anticoagulants)

Inactivate factors V, VIII, & promote fibrinolysis.

May contribute to the transient procoagulant effect of oral anticoagulants when they are first administered.

Onset of Action:

Maximal effect of Oral Anticoagulants is not observed until 3 – 5 days after starting therapy. Usually requires 5 – 7 days to become therapeutic

3.         Identify the most common adverse effect of oral anticoagulants.

Tim, Brenner pg 162

 The most common adverse effect of oral anticoagulants is bleeding, which may range in severity from mild nosebleeds to life-threatening hemorrhage.  Pts should report any bleeding including hematuria and ecchymoses.

Kate Brenner 162

The most common adverse effect of oral anticoagulants is bleeding, which may range in severity from mild nosebleed to life-threatening hemorrhage.  Pts should be instructed to report any signs of bleeding, including hematuria and ecchymoses.

Anonymous Brenner p 163-164

٭         The #1 adverse effect is bleeding, which ranges from mild to (stuck pig) life threatening.

٭         Agranulocytosis

٭         Birth defects

٭         Renal toxicity (rx: Anisindione)

Anonymous  Brenner p. 163

Bleeding, which may range in severity from mild to nosebleed to life-threatening hemorrhage.

Anonymous p. 162

Bleeding: Mild nosebleed to life-threatening hemorrhage

Pt should report any signs of bleeding, including hematuria & ecchymoses.

4.         Recognize that oral anticoagulants are contraindicated in pregnancy, and have a large number of potential drug interactions.

Tim, Brenner pg 162-163

 Contraindicaton in pregnancy: Oral anticoagulants are contraindicated in pregnancy due to their potential to cause fetal hemorrhage and various structural malformations that are collectively referred to as the fetal warfarin syndrome.

Potential drug interactions: most interactions due to induction (rifampin and barbiturates) or inhibition (salicylates+ some 3^rd gen. Cephalosporins) of cytochrome P450 enzymes, and a few are due to the antagonism or potentiation of the anticoagulant effect.

The most serious interactions are w/ drugs that increase the anticoagulation effect and increase the risk for hemorrhage.

Kate Brenner 162

The oral anticoagulants are contraindicated in pregnancy because of their potential to cause fetal hemorrhage and various structural malformations that are collectively referred to as the fetal warfarin syndrome.  These malformations are partly due to antagonism of vitamin K-dependent maturation of bone proteins during a process in which certain proteins undergo carboxylation in the same manner as the nascent clotting factors.  Warfarin and other oral anticoagulants block the process and may cause chondroysplasia punctata and various other birth defects.

Most drug interactions with oral anticoagulants are due to induction or inhibition of cytochrome P450 enzymes, but a few are due to the antagonism or potentiation of the anticoagulant effect.  The most common serious interactions are with drugs that increase the anticoagulant effect and put the patient at risk for hemorrhage.  Because there are so many drugs that interact with oral anticoagulants, pts should be instructed to consult their provider before starting or stopping any other medication.

Anonymous Brenner pg 162

•                  Pregnancy: oral anticoagulants are contraindicated in pregnancy because of their potential to cause fetal hemorrhage and various structural malformations that are collectively called fetal warfarin syndrome.

•                  Drug interactions: Serum levels altered by induced or inhibited cytochrome P450, by drugs that inhibit gut absorption  and by drugs that directly increase or decrease the anticoagulant effect.

•        The most serious interactions are with drugs that increase the anticoagulation effect and place the pt at risk for hemorrhage.(ex: high doses of salicylates or some 3^rd generation cephalosporins.

•        Rifampin or barbiturates induce cytochrome P450 enzymes and decrease anticoagulation effects.

•        Cholestyramine inhibits the absorption of warfin from the guts, along with cimetidine, fluconazole, metronidazole, phenlybutazone, sulfinpyrazone, amiodarone, and trimethoprin-sulfamethoxazole.

•        Phytonadione directly antagonizes the effects of oral anticoagulants on clotting factor synthesis and is used to treat hemorrhage caused by anticoagulant activity.

Anonymous  Brenner 163.

Oral anticoagulants cross the placenta and cause hemorrhage and malformations in fetus.

INTERACTIONS- Most drug interactions are due to induction or inhibition of cytochrome P450 enzymes but a few are due to potentiation of the anticoagulant effect (aspirin) . So, be aware of any drug interactions especially the azoles, barbiturates, amiodarone, cimetidine (now an OTC drug…).

Anonymous p. 162 - 163

Oral anticoagulants cross the placenta and may cause fetal hemorrhage & malformations, Fetal warfarin syndrome, chondrodysplasia punctata & other birth defects (Table 4.6)

Drug Interactions

Most due to induction or inhibition of cytochrome P450 enzymes

Few due to antagonism or potentiation of anticoagulant effect

Most serious interactions w/drugs that increase anticoagulant effect

Lots of Interactive Drugs:

–        Pts to consult physician before starting or discontinuing any other medication(s).

Salicylates in high doses or some 3^rd-generation Cephalosporins: Direct hypoprothrombinemic effect (increases the anticoagulant effect of warfarin & related drugs).

Rifampin or Barbiturates: Induce cytochrome P450 enzymes (decreases the anticoagulant effect of warfarin).

Cholestyramine: Inhibits absorption of warfarin from the gut.

Amiodarone, Cimetidine, Fluconazole, Metronidzaole, Phenylbutazone, Sulfinpyrasone & Trimethoprim-Sulfamethoxazole: Inhibit metabolism of warfarin

Phenylbutazone & Sulfinpyrazone: Directly inhibit clot formation & platelet aggregation.

Phytonadione: Used to treat hemorrhage caused by anticoagulant activity

Directly antagonizes the effect of oral anticoagulants on clotting factor synthesis

5.         Identify the antidote for oral anticoagulants.

Tim, Brenner pg 163 couldn’t find the word antidote in Brenner, this was the closest thing

 Phytonadione directly antagonizes the effect of oral anticoagulants on clotting factor synthesis and is used to treat hemorrhage caused by anticoagulant activity.

Kate Brenner 163, CMDT 1569

The treatment of bleeding may include a reduction in drug dosage and the administration of phytonadione (vitamin K₁).  If bleeding is serious or if the INR is markedly elevated (>20), fresh frozen plasma of factor IX concentrate may be warmed and administered to rapidly replace clotting factors.

Anonymous Brenner, p. 163 and ER med. p. 1406

If bleeding occurs, the oral anticoagulant should be withheld until the bleeding can be evaluated and the patient’s PT can be determined.  The treatment of bleeding may include a reduction in drug dosage and the administration of phytonadione (Vit. K1).  If bleeding is serious or if the INR is markedly elevated (>20), fresh frozen plasma or factor IX concentrate may be warmed and administered to rapidly replace clotting factors.

Emergency Treatment of Bleeding Complications of Antithrombotic Therapy

Anonymous   Brenner, pp. 163

Phytonadione (vitamin K₁) directly antagonizes the effect of oral anticoagulants on clotting factor synthesis and is used to treat hemorrhage caused by anticoagulant activity.

Anonymous

Phytonadione (vitamin K1)

If bleeding serious or INR markedly elevated (>20), fresh frozen plasma or factor IX concentrate may be warmed & administered to rapidly  replace clotting factors.

6.         Identify the indications for use of oral anticoagulants.

Kim R. Brenner 163

Retard coagulation and thereby prevent the occurrence or enlargement of a thrombus.

**these are primarily used in the long-term management of pts who have a thromboembolic disorder such as DVT or atrial fib and pts who have an artificial heart valve.  

They are also used in conjunction with heparin for the treatment of MI.

Goal- is to inhibit embolization and thereby prevent the serous and potentially fatal sequelae of thrombosis.  Oral anticoagulants can keep an established thrombus from extending, but they cannot dissolve one.

Megan Brenner 163

Oral anticoagulants are primarily used in the long term management of patients who have a thromboembolic disorder such as DVT, or atrial fibrillation and patients who have an artificial heart valve.  They are also used in conjuction with heparin for the treatment of MI.  The goal of oral anticoagulant use is to inhibit embolization and thereby prevent the serious and potentially fatal sequelae of thrombosis.  Oral anticoagulants can keep an established thrombus from extending, but they cannot dissolve one.

Anonymous Brenner, p.163 & 165: table 16-4.

Oral anticoagulants are primarily used in the long-term management of patients who have a thromboembolic disorder such as deep vein thrombosis or atrial fibrillation and patients who have an artificial heart valve.  They are also used in conjunction with heparin for the treatment of Myocardial Infarction.  The goal of oral anticoagulant use is to inhibit embolization and thereby prevent the serious and potentially fatal sequelae of thrombosis.  Oral anticoagulants can keep an established thrombus from extending but they cannot dissolve one.

Table 16-4  Clinical Uses of Anticoagulant, Antiplatelet, and Fibrinolytic Drugs

Anonymous   Brenner p. 163

Oral anticoagulants are primarily used in the long-term management of patients who have a thromboembolic disorders such as DVT or Atrial fibrillation and pts who have an artificial heart valve.  Also used in conjunction w/ heparin for the treatment of MI’s

Anonymous p. 163

The goal of treatment is to inhibit embolization, prevent serious & potentially fatal sequelae of thrombosis and keep established thrombus from extending. These will not dissolve a clot.

Primarily Use: (Table 16.4)

Long-term management of pts who have a thromboembolic disorder such as deep vein thrombosis, atrial fibrillation, or artificial heart valve. Also used in conjunction w/heparin to tx myocardial infarction.

7.         Describe the use of the prothrombin time (PT) and international normalized ratio (INR) to monitor oral anticoagulant therapy.

Kim R.  Brenner 163

PT- is a measurement determined by drawing a blood sample, adding a tissue thromboplastin preparation to initiate coagulation in it and comparing the in vitro clotting time in the sample with that in a standardized control preparation.  As a general rule of thumb, the dosage of anticoagulant to be given should prolong the PT of the pt so that it is 1.3 to 1.5 times the PT of the control.

INR-when International reference thromboplastic preparation is used as the standardized control preparation, the ratio is expressed as the INR and is calculated as follows:

            INR+(PT_observed/PT_control)^ISI

This is where the PT times of the patient and control respectively and the ISI is the (international sensitivity index) of the thromboplastin reagent being used.  For most indications, an INR of 2-3 is recommended.  However, for the pts with mechanical prosthetic heart valves and for those with recurrent systemic embolization, an INR pf 3 to 4 is recommended.

The pts PT should be monitored daily during the initiation of therapy and whenever another drug is added to or withdrawn from the treatment regimen.

Megan Brenner 163

The dosage of oral anticoagulants to be given is based on the patients prothrombin time (PT).  This measurement is determined by drawing a blood sample, adding tissue thromboplastin preparation to initiate coagulation in it, and comparing the in vitro clotting time in the sample with that in a standardized control preparation.  As a general rule of thumb, the dosage of anticoagulant to be given should prolong the PT of the patient so that it is 1.3-1.5 times the PT of the control.

When the international reference thromboplastin preparation is used as the standardized control preparation, the ration is expressed as the international normalized ratio (INR) and is calculated:

INR= (PT_observed/ PT_control)^ISI  where PT_observed and PT_control are prothrombin times of the patient and control respectively, and the ISI is the international sensitivity index of the thromboplastin reagent being used.  For the most indications, an INR of 2-3 is recommended.  This can change for patients with a prosthetic heart valve and recurrent systemic embolization, their recommended INR is higher-3-4.5.

Anonymous Brenner, p. 163

The dosage of oral anticoagulants to be given is based on the patient’s prothrombin time (PT).  This measurement is determined by drawing a blood sample, adding a tissue thromboplastin preparation to initiate coagulation in it, and comparing the in vitro clotting time in the sample with that in a standardized control preparation.  

As a general rule of thumb, the dosage of anticoagulant to be given should prolong the PT of the patient so that it is 1.3-1.5 times the PT of the control.

PT is the time taken for clotting of citrated plasma after the addition of Ca2+ and standardized reference thromboplastin, and expressed as the ratio of the PT of the patient to the PT of a pool of healthy subjects on no medication.

The INR or international normalized ratio is a common scale designed to take account of differences between laboratories:  the sensitivity of the local method is expressed as an index, the international sensitivity index  (ISI), which is the slope of a logarithmic plot of PT obtained using the primary international reference preparation of thromboplastin against PT obtained with the local standard.  INR is calculated as (PT ratio):  INR = (PTobserved/PTcontrol)ISI.  These are the prothrombin times of the patient and control, respectively.  For most indications, an INR of 2-3 is recommended.  However, for patients with mechanical prosthetic heart valves and for those with recurrent systemic embolization, an INR of 3-4.5 is recommended.

The patient’s PT should be monitored daily during the initiation of therapy and whenever another drug is added to or withdrawn from the treatment regimen.  Concurrent heparin therapy may cause an increase of 10-20% in the patient’s PT, so the target PT and INR levels should be increased by the same amount.  Once the patient’s PT has stabilized, it should be monitored every 4-6 weeks.

Anonymous   Brenner p. 163

The dosage of oral anticoagulants to be given is based on the patient's prothrombin time (PT). Drawing a blood sample, adding a tissue thromboplastin preparation to initiate coagulation in it, and comparing the in vitro clotting time in the sample with that in a standardized control preparation determine this measurement. As a general rule of thumb, the dosage of anticoagulant to be given should prolong the PT of the patient so that it is 1.3‑1.5 times the PT of the control.

When the international reference thromboplastin preparation is used as the standardized control preparation, the ratio is expressed as the international normalized ratio (INR) and is calculated as follows:

INR = (PT observed / PT control) ^ISI

Where the PT-observed and PT-control are the prothrombin times of the patient and control, respectively, and the ISI is the international sensitivity index of the thromboplastin reagent being used. For most indications, an INR of 2‑3 is recommended. However, for patients with mechanical prosthetic heart valves and for those with recurrent systemic embolization, an INR of 3‑4.5 is recommended.

The patient's PT should be monitored daily during the initiation of therapy and whenever another drug is added to or withdrawn from the treatment regimen. Concurrent heparin therapy may cause an increase of 10‑20% in the patient's PT, so the target PT and INR levels should be increased by the same amount. Once the patient's PT has stabilized, it should be monitored every 4‑6 week.

Anonymous p. 163

General Rule of Thumb

Dosage should prolong PT of the Pt. 1.3 – 1.5 times the PT of the control.

When the international reference thromboplastin preparation is used as the standardized control preparation the ratio is expressed as the International Normalized Ratio (INR).

Calculated as: INR = (PT observed / PT control)^ISI

PTobserved / Ptcontrol= Prothrombin times of the pt and control respectively.

 ISI= International sensitivity index of thromboplastin reagent being used.

Most indications

  INR of 2 - 3 is recommened.

Mechanical prosthetic heart valves & recurrent systemic embolization

   INR of 3 – 4 is recommended

PT should be monitored daily during the initiation of tx and whenever another drug is added to or withdrawn from the tx regimen.

Concurrent Heparin tx may cause an increase of 10-20% in pt’s PT so target PT and INR levels should be increased by the same amount.

Once Pt’s PT has stabilized, it should  be monitored Q 4 – 6 wks.

8.         Briefly state the mechanism of action of parenteral anticoagulants and the time frame necessary for onset of action.  (representative drugs: heparin, enoxaparin)

Kim R.  Brenner 165

Heparin- inactivates clotting factors.  The predominant effect of unfractionated heparin is to potentiate the activity of an endogenous anticoagulant called antithrombin III (AT-III).  This substance then inactivates thrombin and other clotting factors.

Enoxaprin and dalteparin directly inactivate factor Xa and have less direct effect on thrombin via activation of AT-III.

Megan Brenner 164-165

Heparin is a naturally occurring mixture of sulfated mucopolysaccharides produced by mast cells and basophils. In its natural form it contains fractions with high molecular weights and low molecular weights. Enoxaparin is a low molecular weight form of fractionated heparin. It can be obtained from porcine intestine or bovine lung.

Mechanism of action: Heparin inactivates clotting factors.  The predominat effect of unfractionated heparin is to potentiate the activity if an endogenous anticoagulant, antithrombin III.  This substance then inactivates thrombin and other clotting factors.  Enoxaparin directly inactivates factor Xa and has less direct effect on thrombin .

On set of action:  Heparin must be given parenterally, usually by continous intravenous infusion, it has a half life of 90 minutes. A dosage is considered adequate when PTT is 1.5-2 times normal.  Enoxaparin is usually give subcutaneously and maximal effect occurs from 3-5 hours after injection.

Anonymous Brenner 164-65

Heparin inactivates clotting factors.  The predominant effect of unfractionated heparin is to potentiate the activity of an endogenous anticoagulant called antihrombin III (AT-III).  This substance then inactivates thrombin  (factor IIa) and other clotting factors.  (see Fig. 16-3c).  Enoxaparin (Lovenox) and dalteparin (Fragmin) directly inactivate factor Xa and have less direct effect on thrombin via activation of AT-III.  

Heparin is not absorbed from the gut and must be given parenterally.  It is usually administered by continuous IV infusion.  It is removed from circulation by the reticuloendothelial system (which includes the histiocytes in the skin and subcutaneous layer, stellate reticuloendothelial cells (Kupffer cells) in the liver, alveolar macrophages in the lungs, micorglia in the nervous system, and tissue macrophages in the spleen, lymph nodes and red bone marrow.), is eliminated by the renal and hepatic mechanisms, and has a half-life of 90 minutes.  Enoxaparin and deltaparin are usually administered subcutaneously and their maximal effect occurs from 3-5 hr after injection.  When they are used, the aPTT does not need to be monitored.

Anonymous  

Heparin—inactivates clotting factors.  The predominant effect of unfractionated heparin is to

potentiate the activity of an endogenous anticoagulant called antithrombin III (factor IIa) and other clotting factors.

•        is not absorbed from the gut and must be given parenterally.  

•        It has a relatively immediate effect of potentiating the effects of AT III, & has a 1/2t of about 90 minutes

•        Doseage is generally determined by monitoring activated PTT and is considered adequate when the aPTT is 1.5-2 times normal

Enoxaparin—directly inactivates factor Xa (which inhibits the conversion of prothrombin to thrombin figure 16-2, pg. 161).

•         administered subcutaneously, and their maximal effect occurs from 3 to 5 hours after injection.

Does not require monitoring of the aPTT.

Anonymous p. 165

MOA    Fig 16.2   p. 161

Heparin  (Usually Continuous IV Infusion) inactivates clotting factors via activation of antithrombin III (AT-III)   

Enoxaparin & Dalteparein  (Usually SQ administration) directly inactivate factor Xa and

have less direct effect on thrombin via activation of AT-III

Unfractionated Heparin  

Primarily inactivates thrombin by activating antithrombin III.

Fractionated Heparin

Primarily inactivates factor Xa

Onset of Action

Heparin

½ life of about 90 minutes

Enoxaparin & Dalteparin

Maximal effect occurs from 3 – 5 hrs after injection

9.         Identify the most common adverse effects of parenteral anticoagulants.

Kim R. Brenner 164

Dalteparin- bleeding and thrombocytopenia.

Enoxaprin- bleeding and thrombocytopenia.

Heparin- bleeding, hyperkalemia, and thrombocytopenia.

Hirudin and related drugs- Bleeding.

Megan Brenner 165

The most common side effects of fractionated and unfractionated heparin is bleeding.  Thrombocytpenia and hyperkalemia my also occur, with hyperkalemia usually due to the suppression of aldesterone secretion.

Anonymous Brenner, p.165

Hemorrhage is the most hazardous SE of parenteral anticoagulants

Enoxaparin-  bleeding and thrombocyotpenia

Heparin-  bleeding, hyperkalemia, and thrombocytopenia.

Anonymous  Brenner, p.164

Bleeding, thrombocytopenia, hyperkalemia

Anonymous Table 16.3   p. 164   p. 165

The most common serious adverse effect of fractionated & unfractionated heparin is bleeding

Other Adverse Effects: thrombocytopenia and hyperkalemia (usually due to suppression of aldosterone secretion)

10.       Identify the indications for use of parenteral anticoagulants.

Kim R. Brenner 165

Heparin is indicated for the TX of acute thromboembolic disorders, including peripheral and pulmonary embolism, venous thrombosis, and coagulopathies such as disseminated intravascular coagulation (DIC).  It is used prophylactially to prevent clotting in arterial and heart surgery, during blood transfusions, and in renal surgery, blood sample collection.  Heparin is also used to prevent embolization of thrombi that may cause a cerebrovascular event in pts with acute A-fib.  Low doses of heparin may be administered subcutaneously to prevent DVT and PE in high-risk pts.

Enoxaprin or dalteparin can be administered subcutaneously to prevent DVT following hip replacement surgery.

Megan Brenner 165

Heparin is indicated for the treatment of acute thromboembolic disorders, including peripheral and pulmonary embolism, venous thrombosis, and coagulopathies such as disseminated intravascular coagulation.  It is used prophylactically to prevent clotting in arterial and heart surgery during transfusions and in renal dialysis and blood sample collection.  Heparin can be used to prevent embolism of thrombi that may cause a cerebralvascular event in patients with acute atrail fibrillation.  Low doses of heparin may be administered subcutaneously to prevent deep vien thrombosis and pulmonary embolism in high risk patients.  

Enoxaparin can be administered subcutaneously to prevent deep vein thrombosis following hip surgery.

Anonymous Brenner, p. 165

Indicated for treatment of acute thromboembolic disorders: peripheral and pulmonary embolism, venous thrombosis, and coagulopathies such as disseminated intavascuolar coagulation.  IT is used prophylactically for prevention of clotting in arterial and heart surgery, during blood transfusions, and in renal dialysis and blood sample collection.  Heparin is also used to prevent embolization of thrombi that may cause a cerebrovascular event in patients with acute atrial fibrillation.  Low doses of heparin may be administered subcutaneously to prevent deep vein thrombosis and pulmonary embolism in high-risk patients.  Enoxaparin can be given subcutaneously to prevent DVT post-op THA (total hip arthroplasty).

Anonymous  Brenner pg. 165

Indicated for treatment of acute thromboembolic disorders.

These include peripheral and pulmonary embolism, venous thrombosis, and coagulopathies such as DIC. May be used prophylactically for prevention of clotting in arterial and heart surgery, during blood transfusions, and in renal dialysis and blood sample collection. May be used to prevent thrombi formation in atrial fib.

Anonymous p. 165

Heparin

Acute thromboembolic disorders ie. peripheral venous thrombosis & pulmonary embolism

Coagulopathies such as Disseminated Intravascular Coagulation (DIC)

Prophylactically to prevent clotting in arterial & heart surgery, during blood transfusions, in renal dialysis, and in blood sample collection.

Prevent embolization of thrombi that may cause CVA in pts w/acute atrial fibrillation

Low Doses of Heparin - May be administered SQ to prevent  deep vein thrombosis & pulmonary embolism in high-risk pts.

Enoxaparin or Dalterparin

Can be administered SQ to prevent deep vein thrombosis following hip replacement surgery.

11.       Describe the use of the activated partial thromboplastin time (aPTT) to monitor heparin therapy.

Greg  CMDT p.285

Heparin clearance is dose-dependent; it is highly protein-bound; and a minimum/threshold level is necessary to achieve an antithrombotic effect.  It is necessary to monitor the aPTT and adjust dosing to maintain the aPTT to 1.5-2.5 times control.

Stephen Brenner pg 165

The dosage of heparin is generally determined by monitoring the aPTT. The dosage is considered adequate when the aPTT is 1.5-2 times normal.

Ky, Brenner p165

PTT used to monitor heparin dose. Heparin must be given parenterally b/c it’s not absorbed in gut.  ½-life = 90 minutes.  The doseage is considered adequate when the PTT is 1.5 to 2x normal.

Paul, Brenner pg 165

The dosage of heparin is generally determined by monitoring the activated partial thromboplastin time.

Anonymous Brenner, p. 165

The dosage of Heparin is generally determined by monitoring the activated partial thromboplastin time (aPTT).  The dosage is considered adequate when the aPTT is 1.5-2 times normal. (The dose of unfractionated heparin is adjusted to achieve a value within a target range.

Anonymous  Ravel, pg. 89.

The PTT was useful in detecting intrinsic factor abnormalities but was relatively insensitive to effects of heparin. Adding certain "contact activators" (usually chemicals or particulate matter, such as kaolin) to the PTT reagent was found to activate factor XII (contact factor) swiftly and uniformly and thus eliminate another variable in the clotting process. In addition, the activated APTT was found to be sensitive to heparin. The APTT is very sensitive to coagulation factor deficiencies within the intrinsic system before the prothrombin to thrombin stage. It may also be abnormal in prothrombin or fibrinogen deficiencies but only if the defect is relatively severe (prothrombin or fibrinogen/fibrin abnormalities may affect the test because the test depends on fibrin clot formation as the reaction end point). The APTT is not as sensitive to prothrombin abnormalities as the PT because the extrinsic thromboplastin used in the PT test is more powerful than the intrinsic system prothrombin activator complex generated by the APTT, thus enabling the PT to demonstrate relatively smaller defects in prothrombin. Platelet abnormalities do not influence the APTT.

Anonymous CMDT – Page 283

Heparin dose is generally determined by monitoring the activated Partial Thromboplastin Time (aPTT). Dosage is considered adequate when aPTT is 1.5 – 2 times normal.

Dosage to maintain the a PTT 1.5 – 2.5 times control.

12.       Identify advantages of low-molecular-weight heparins vs. unfractionated heparin.

Greg  CMDT p. 285

Low-molecular weight heparins are depolymerized preparations of heparin with multiple advantages over unfractionated heparin:

- They exhibit less binding to cells & proteins

- Have superior bioavailability

- Longer plasma ½ life (t_1/2)

- Have more predicable dose-response characteristics

- They appear to carry and equivalent or lower risk of hemorrhage

- Immune-mediated thrombocytopenia is less common

- At least equally effective in the treatment of venous thromboembolism

- Administered in doses based on body wgt qd or bid w/o need for coagulation monitoring

- SubQ admin seems to be as effective as IV

+ All the above make LMW heparins ideal for home-based therapy.

SV/Peripheral Venous handout. Pg.9.

Advantages of low-molecular heparin:

1.      Longer half-life

2.      Useful for outpatient treatment

3.      NOT followed with PTT

4.      Less risk of bleeding complications

Stephen Brenner pg 165

Heparin inactivates clotting factors. The predominant effect of unfractionated heparin is to potentiate the activity of an endogenous anticoagulant called antithrombin III (AT-III). Administered by IV route.

Dr Evan’s handout

Heparin enhances the effect of antithrombin, thus interferes with clotting. Effects are short term and fast.

Brenner pg 165

Low-molecular weight heparins (Enoxaparin and dalteparin) directly inactivate factor Xa and have less effect on thrombin via activation of AT-III. Usually administered SQ and their maximal effect occurs from 3-5 hours after injection. The aPTT does not need to be monitored. Can be self administered by patient at home.

Ky, Brenner p164-65

Low MW: (enoxaparin & dalteparin). Less direct effect on thrombin by activation of AT-III.

Unfractionated: potentiate the acivity of AT III.  AT-III inactives thrombin and other clotting factors.

Paul, Brenner pg 165

Advantages of low-molecular-weight heparins:

• Directly inactivate factor Xa and have less direct effect on thrombin via activation of AT-III

• Usually administered subcutaneously, and their maximal effect occurs from 3-5 hours after injection.

• When used, the aPTT does not need to be monitored

• Can be administered subcutaneously to prevent deep vein thrombosis following hip replacement surgery

Anonymous. Brenner 165

Low molecular weight forms of unfractionated heparin directly inactivate factor Xa and have less direct effect on thrombin via activation of AT-III.  It is usually administered subcutaneously, and maximal effects occur from 3-5 hours after injection.  When they are used, the aPTT does not need to be monitored.  Can be administered subcutaneously to prevent deep vein thrombosis following a hip replacement surgery.

Anonymous   Brenner, p. 165.

Unfractionated                                                                                               LMW Heparin

Potentiates activity of Endogenous anticoagulant Antithrombin-III.                     Directly inactivates factor Xa.

Not absorbed from the gut                                                                   

Administered by continuous IV                                                             Administered Sub Q.

t-1/2 = 90 minutes                                                                                            Maximal effect in 3 – 5 hrs.

            Must be monitored by Activated Partial Prothrombin Time (aPTT).       aPTT does not need to be measured.

Anonymous CMDT Page 285, Table 9.24 LMW Heparin Regimens

Exhibit less binding to Cells & Proteins

Have Superior Bioavailability

Longer Plasma Half-Life

More Predictable Dose-Response Characteristics

Appear to carry an Equivalent or Lower Risk of Hemorrhage

Immune mediated thrombocytopenia is Less Common

At least as Effective as Unfractionated Heparin  in Tx of Venous Thromboembolism

Dosages Determined by Body Wt. QD or BID w/o need for coagulation  monitoring

SQ administration appears to be As Effective as IV route.

Ideal for Home-Based Tx of Venous Thromboembolism in small number of selected pts.

13.       Identify the antidote for heparin-induced hemorrhage.

Greg  Brenner p. 165

Tx consists of administration of protamine sulfate (it is (+) protein that inactivates (-) heparin).  Protamine is admin by IV and dosage is based on the estimated amount of residual heparin in the body.  Severe bleeding may require the adimin of fresh frozen plasma (FFP).

SV/ Brenner 165

Protamine Sulfate. Fresh frozen plasma for severe bleeding.

Stephen Brenner pg 165

Treatment of heparin-induced hemorrhage consists of administering protamine sulfate, which is a positive charged protein that physically combines with negatively charged heparin and thereby inactivates it. Protamine is administered IV for this purpose and the dosage is based on the estimated amount of residual heparin in the body. Severe bleeding may require the administration of fresh frozen plasma.

Ky, Brenner p165

Antidote = protamine sulfate (IV). Dosage based on estimated amount of residual heparin.

Paul, Brenner pg 165

The treatment of heparin-induced hemorrhage consists of administering protamine sulfate, which is a positively charged basic protein that physically combines with negatively charged heparin and thereby inactivates it.  Protamine is administered intravenously for this purpose, and the dosage is based on the estimated amount of residual heparin in the body.  Severe bleeding may require the administration of fresh frozen plasma.

Anonymous  Brenner 165

Protamine sulfate IV, dosage is based on the estimated amount of residual heparin and the body.  Severe bleeding may require administration of fresh frozen plasma.

Anonymous    Noble, pg. 1050

Heparin anticoagulation may be rapidly reversed with protamine sulfate, given at a ration of 1 mg per 100 units of estimated heparin reserve (the amount of heparin thought to remain in the body).

Anonymous

Protamine Sulfate (IV administration)

Dose based on the estimated amount of residual heparin in the body.

It inactivates heparin

14.       Describe the use of aspirin as an antiplatelet drug; identify indications, common adverse effects, and interactions.

Greg  Brenner pp164-166

ASA inhibits platelet aggregation & is used to prevent & tx arterial thromboembolic disorders.

Indications:

Common Adverse Effects:

- High doses can increase likelihood of bleeding via a direct hypoprothrombinemic effect that can ↑ the anticoag effect (impaired hemostasis).

- GI bleeding and Irritation (it inhibits the synthesis of pg’s that promote secretion of bicarb & mucus that protect the mucosa from stomach acid and pepsin.

- Hypersensitivity rxns

- Tinnitus

Interactions:

- ↑ hypoglycemic effect of sulfonylureas

- ↑ risk if GI bleed and ulceration assoc w/ methotrexate, valproate, & other drugs.

- Inhibits uricosuric (excretion of uric acid in the urine) effect of probenecid.

SV/Brenner 164

Common Adverse effects:Gastrointestinal irritation and bleeding, hypersensitivity reactions, and tinnitus.

Interactions:  Increased hypoglycemic effect of sulfonylures.  Increases risk of gi bleeding and ulceration assoc. with methotrexate, valproate, and other drugs.  Inhibits uricosuric effect of probenecid.

Stephen Brenner pg 166

Aspirin inhibits platelet aggregation and is used in the prevention and treatment of arterial thromboembolic disorders.

…primarily used to prevent arterial thrombosis in pts with ischemic heart disease and stroke, but it has many other indications as well. In pts with unstable angina, it is used to prevent enlargement of a coronary thrombus and potentially reduce the severity of cardiac damage. In pts with transient ischemic attacks, it can be used to prevent an initial or subsequent stroke. In pts who have artificial heart valves or are undergoing percutaneous transluminal coronary angioplasty, it is used to prevent thrombosis.

Adverse effects and interactions:

…may cause bleeding, especially in the gastrointestinal tract, where it inhibits secretion of bicarbonate and mucus.

…hypersensitivity reactions, and tinnitus.

Increases hypoglycemic effect of sulfonylureas.

Increases risk of GI bleeding and ulceration associated with methotrexate, valproate, and other drugs.

Inhibits uricosuric effect of probenecid.

Ky, Brenner p164-66

Indications: ischemic heart dz and stroke. TIA. Pts with artificial heart valves and undergoing angioplasty to prevent thrombosis.  In pts with unstable angina it’s used to prevent MI. Used for recent MI to prevent enlargement of coronary thrombus and ↓ severity of damage.

Adverse Effects: may cause bleeding (GI and other). Hypersensitivity rxns. Tinnitus.

Interactions: ↑ hypoglycemic effects of sulfonylureas. ↑ risk GI bleeds/ulceration with methotrexate, valporoate and others.  Inhibits uricosuric effect of probenecid.

Paul, Brenner pg 166

Indications:

• Prevent arterial thrombosis in patients with ischemic heart disease and stroke

• Patients with unstable angina to prevent myocardial infarction

• Patients with recent MI, it is used to prevent enlargement of a coronary thrombus and potentially reduce he severity of cardiac damage

• Patients with transient ischemic attack to prevent an initial or subsequent stroke

• Patients with artificial heart valves to prevent thrombus

• Patients undergoing percutaneous transluminal coronary angioplasty to prevent thrombus

Common adverse effects:

• Bleeding, especially GI tract, where it inhibits the synthesis of prostaglandins that promote secretion of bicarbonate and mucus

• Gastric irritation

• Hypersensitivity reactions

• Moderately high doses can cause tinnitus (abnormal auditory sensation or noise)

Interactions:

• High doses of aspirin and other salicylates have a direct hypoprothrombinemic effect that may increase the anticoagulant effect and thereby increase the likelihood of bleeding

Anonymous Brenner 166, 164 table 16-3

            Aspirin is the only NSAID that irreversibly inhibits cyclooxygenase, the enzyme that catalyzes an early step in TXA₂ synthesis (TXA₂ becomes predominant during thrombus formation).  

            Indications: Aspirin is primarily used to prevent arterial thrombosis in patients with ischemic heart disease and stroke, but it has many other indications as well.  In patients with unstable angina, it is used to prevent myocardial infarction.  In patients with recent myocardial infarction, it is used to prevent enlargement of a coronary thrombus and potentially reduce the severity of cardiac damage.  In patients with transient ischemic attacks, it can be used to prevent an initial or subsequent stroke.  In patients with artificial heart valves or are undergoing percutaneous transluminal coronary and angioplasty, it is used to prevent thrombosis.

            Adverse effects: May cause bleeding, especially in the gastrointestinal tract, where it inhibits the synthesis of prostaglandins that promotes secretion of bicarbonate and mucus.  High doses of aspirin and other salicylates have direct hypoprothrombinemic effect that may increase the anticoagulant effect and thereby increase the likelihood of bleeding.

            Interactions: Increases hypoglycemic effect of sulfonylureas.  Increases the risk of gastrointestinal bleeding and ulceration associated with methotrexate, valproate, and other drugs.  It inhibits uricosuric effect of probenecid.

Anonymous  

Mechanism of action- low doses of aspirin have been found to selectively inhibit the synthesis of TXA2 without having much effect on prostacyclin (TXA2 promotes platelet aggregation, prostacyclin inhibits platelet aggregation). At higher doses, aspirin inhibits both.

Indications- used to prevent arterial thrombosis in patients with ischemic heart disease and stroke. Also indicated in patients with unstable angina (to prevent MI), in patients with recent MI (to prevent enlargement of coronary thrombus), in patients with TIA (can prevent initial or subsequent stroke) and in patients who have artificial heart valves or are undergoing PTCA (to prevent thrombosis).

Common adverse effects- bleeding, especially in GI tract, hypersensitivity reaction, tinnitus.

Interactions- increases hypoglycemic effect of sulfonylureas. Increases risk of GI bleeding and ulceration associated with methotrexate, valproate and other drugs. Inhibits uricosuric effect of probenecid. Brenner, pp 164-166

Anonymous CMDT – Page 350

All pts w/definite or suspected MI should receive aspirin at a dose of 162mg or 325mg at once, regardless of whether thrombolytic tx is being considered or the pt has been taking aspirin. Chewable aspirin provides more rapid blood levels.

Aspirin inhibits platelet aggregation for the life of the platelet   Brenner – p. 166.

Indications:

Prevention & tx of arterial thromboembolic disorders

Prevent arterial thrombosis in pts w/ischemic heart disease & stroke

Prevent myocardial infarction in pts w/unstable angina

Prevent enlargement of a coronary thrombus and potentially reduce the severity of cardiac damage in pts w/recent myocardial infarction

Prevent initial/subsequent stroke in pts w/transient ischemic attacks

Prevent thrombosis in pts who have artificial heart valves or are undergoing percutaneous transluminal coronary angioplasty.

Adverse Effects:

Bleeding, especially in the gastrointestinal tract

Reye’s Syndrome in children Brenner – Chptr 30  p. 322

Excessive doses may cause hypoprothrombinemic effect that impairs hemostasis & causes bleeding

Anaphylactic Reactions

Vasomotor Rhinitis

Angioedema

Urticaria (hives)

Tinnitus

See Table 16.3  - p. 164  for Common Drug Interactions

15.       Identify the indications for use of fibrinolytic drugs.  (representative drugs: streptokinase, alteplase)

 Greg  Brenner p167

They are primarily used to dissolve clots in pt’s undergoing MI, thrombotic stroke, or PE.  These drugs can also be used to dissolve an existing thrombus.  Recent studies suggest their use in pt’s w/ acute ischemic (thrombotic) stroke may reduce the incidence of the neurologic sequelae of stroke.

SV/Brenner 168

These drugs can be used to dissolve an existing thrombus.  They are primarily used to dissolve clots in patients undergoing MI, Trombotic stroak, or PE. Streptokinase-can cause various types of hypersensitivity reactions, including fatal anaphylactic shock.  For this reason, it should not be used repeatedly in the same patient.

Stephen Brenner pg 167

Unlike the anticoagulant and antiplatelet drugs, these drugs can be used to dissolve an existing thrombus. They are primarily used to dissolve clots in pts undergoing myocardial infarction, thrombotic stroke, or pulmonary embolism.

Ky, Brenner p167

Indications: used to dissolve existing thrombus.  Acute MI, thrombotic stroke, pulmonary embolism.  Use during stroke likely ↓ neurological sequelae.

Paul, Brenner pg 167

These drugs can be used to dissolve an existing thrombus.  They are primarily used to dissolve clots in patients undergoing myocardial infarction, thrombotic stroke, or pulmonary embolism.  Recent studies suggest that their use in patients with acute ischemic (thrombotic) stroke may reduce the incidence of the neurologic sequelae of stroke.

Anonymous Brenner 167

They are primarily used to dissolve clots in patients undergoing myocardial infarction, thrombolytic stroke, or pulmonary embolism.  Recent studies suggest that their use in patients with acute ischemic (thrombotic) stroke may reduce the incidence of neurologic sequelae of stroke.

Anonymous  

-They are used to dissolve an existing thrombus.

-To dissolve clots in pt. Undergoing MI., thrombotic stroke, or PE.

Anonymous

Alterplase

Recombinant form of human tissue plasminogen activator (t-PA)

Streptokinase

Protein obtained from streptococci

Fibrolytic drugs stimulate fibrin degradation and are used to dissolve existing thrombus in pts undergoing myocardial infarction, thrombotic stroke, or pulmonary embolism

16.       Identify the most common adverse effect of fibrinolytic drugs.

Jennyb Brenner 164

The most common adverse side effects of fibrinolytic drugs are bleeding, hypersensitivity reactions, and reperfusion arrythmias.

Amy, Brenner

Hemorrage. Fibrinolytic drugs create a general lytic
state that may lyse both normal and pathologic
thrombi.

SV/ Brenner 168

The most common adverse effect is hemorrhage.

Anonymous Brenner 164 table 16-3

Bleeding, hypersensitivity reactions, and reperfusion anemias.

Anonymous  

The most common AE is hemorrhage – less common in recombinant forms of t-PA (alteplase & reteplase) than streptokinase.

 Arrhythmias such as bradycardia and tachycardia (believed to be caused by free radicals generated in coronary artery reperfusion). STREPTOKINASE can cause hypersensitivity reactions, including fatal anaphylactic shock and therefore should not be used repeatedly in the same patient.

Anonymous Table 16.3 List Adverse Effect & Drug Interactions

Most common adverse effect is hemorrhage

Arrhythmias such as bradycardia and tachycardia

Hypersensitivity reactions w/streptokinase including anaphylactic shock

17.       Identify two potential advantages of t-PA drugs over streptokinase.

Jennyb Brenner 167-168

t-PA is an enzyme that selectively activates plasminogen that is bound to fibrin.  Because of this, it may cause fewer cases of hemorrhage then streptokinase.  Streptokinase is not an enzyme and must combine with plasminogen to form an activator complex that converts inactive plasminogen to plasmin-takes longer-

Amy, Brenner

t-PA selectively activates plasminogen that is bound
to fibrin, therefore may cause fewer cases of
hemorrhage.  Streptokinase may cause hypersensitvity
reactions including fatal anaphylactic shock.

Anonymous.  Brenner 168

Because t-PA selectively activates plasminogen that is bound to fibrin, the recombinant forms of t-PA may cause fewer cases of hemorrhage than streptokinase causes.

Anonymous  Brenner Chp. 16 p.168

1) t-PA drugs may cause less hemorrhaging than streptokinase.

2) Streptokinase can cause various types of hypersensitivity reactions including anaphylactic shock.

Anonymous CMDT - Page 351

t-PA is a naturally occurring thrombolytic factor  that is theoretically thrombus-specific

30-day mortality rate w/t-PA was one absolute percentage point lower (one additional life save per 100 pts Tx) than w/streptokinase

Marginally more effective than streptokinase

18.       Identify the antidote for bleeding caused by fibrinolytic drugs.

Jennyb Brenner 168

Aminocaproic acid inhibits fibrinolysis.  This drug is used to stop bleeding by fibrinolytic drugs.  Interesting enough, it is used in pts with hemophilia as well to stop bleeding.

Amy, Brenner

Aminocaproic acid competitively blocks plasminogen
activation and inhibits fibrinolysis.  Administered
orally or IV.
Anonymous Brenner 168

            Aminocaproic acid inhibits fibrinolysis by competitively blocking plasminogen activation.  This drug is used to stop the bleeding caused by fibrinolytic drugs.  Can be a diminished orally or intravenously and is excreted by the kidneys.

Anonymous  Brenner p. 168

By competitively blocking plasminogen activation aminocaproic acid inhibits fibrinolysis.  This drug is used to stop the bleeding caused by fibrinolytic drugs.  It is used to prevent bleeding in pts. who have hemophilia, are recovering from GI or prostate surgery and those who have cancer and are undergoing radiation therapy or chemotherapy.  

Aminocaproic acid can be adm. orally or by IV and is excreted by the kidneys. Adverse effects- thrombosis hypotension and arrhythmias.    

Anonymous See Fig 16.6  p. 167, Fig 16.1 Normal Hemostasis, Table 16.1 Coagulation Factors, Fig 16.2 Blood Coagulation & sites of Drug Action

Aminocaproic Acid (Oral or IV administration)

Inhibits Fibrinolysis and stops bleeding caused by fibrinolytic drugs