anticoagulants etc. DSA Flashcards
Unfractionated Heparin summary
parenteral
IV, SQ
With antithrombin III binds and inactivates clotting factors IIa, Xa, IXa, XIa, XIIa, Kallikrein
Intrinsic and Common pathways Binds antithrombin III, inhibits Xa
Side effects: bleeding, thrombocytopenia
Low MW Heparin summary
parenteral
SQ
Binds antithrombin III, inhibits Xa
side effect: bleeding
Warfarin summary
slow, sustained oral anticoagulation
Inhibits vitamin K-dependent modification of clotting factors prothrombin, VII, IX, X, protein C and S; Extrinsic and Common pathways
Side effects: bleeding, drug-drug interactions
Low Molecular Weight Heparins (LMWH) include:
- Enoxaparin (Lovenox)
- Dalteparin (Fragmin)
- Tinzaparin (Innohep)
Factor Xa Inhibitors
• Fondaparinux (Arixtra): a synthetic analog of heparin, inhibits factor Xa; injected SQ,
Rivaroxaban, Apixaban, Edoxaban- oral, monitoring not required
“x against X”
coagulation pathway overview
. Both intrinsic and extrinsic pathways generate an active proteolytic enzyme, factor Xa, which in the final common pathway combines with other factors (V, Ca++, and phospholipids) and converts an inactive proenzyme, prothrombin, into its active enzyme product, thrombin. Thrombin clips fragments from the protein fibrinogen releasing fibrin monomers which polymerize into a meshwork that stabilizes the initial platelet plug. Factor XIII, activated by thrombin to XIIIa, covalently cross links adjacent fibrin monomers to form an insoluble fibrin clot.
Therapeutic Objectives in Thromboembolic Disease
To prevent formation of pathological thrombi in patients at risk.
B. To prevent clot extension and/or embolization in patients who have developed thrombosis.
C. To rapidly dissolve thrombi causing life-threatening or severe ischemia.
General Classes of Agents
anticoagulants
antiplatelets (antithrombotic)
fibrinolytic (thrombolytic)
Anticoagulant Drugs
(these agents slow clotting time and suppress coagulation)
1. Heparin, Low Molecular Weight Heparin, and Fondaparinux
- for rapid parenteral (IV, SQ) anticoagulation.
2. Warfarin (Coumadin) for slow, prolonged, oral anticoagulation
3. Direct Thrombin Inhibitors
– dabigatran, rivaroxaban, apixaban, edoxaban - Oral
– lepirudin, bivalirudin, argatroban –IV during PCI
Antiplatelet Drugs (Antithrombotic)
inhibit platelet adhesion and aggregation,
• Aspirin – inhibit TXA2 formation
• Clopidogrel, Ticlopidine, and Prasugrel – inhibit platelet ADP receptor and platelet aggregation
• Cilostazol – cAMP PDE inhibitor, blocks platelet aggregation and stimulates vasodilation
• Abciximab, eptifibatide, tirofiban – blockers of glycoprotein IIb/IIIa complex.
Fibrinolytic (Thrombolytic) Drugs
dissolve formed fibrin clots
t-PA = tissue plasminogen activator
Alteplase (t-PA), reteplase, tenecteplase, streptokinase.
Low Molecular Weight Heparins (LMWH) structure
are the smaller fragments separated from heparin. These compounds differ from unfractionated heparin in their size, antithrombotic and pharmacokinetic properties, adverse effect profiles, and monitoring requirements.
Heparin Mechanism
Antithrombin III is a protein synthesized by the liver and which circulates in the plasma. It rapidly inhibits thrombin but only in the presence of heparin or naturally occurring heparin-like molecules. Heparin inhibits activated coagulation factors of the intrinsic and common pathways, including thrombin, Xa, IXa, XIa, XIIa, and kallikrein. However, it has little or no activity against factor VIIa (extrinsic pathway). Inhibition of thrombin and factor Xa are most important in the anticoagulant effect. Heparin increases the rate of the thrombin antithrombin reaction by serving as a catalytic template to which both the antithrombin and thrombin (or other protease) bind.
***Heparin prolongs both the aPTT and the thrombin time; the PT is less effected, but at high plasma concentrations will also prolong the PT.
Heparin Pharmacokinetics and Routes of Administration
- Because heparin is a large molecule and is destroyed in the GI tract, it can only be administered intravenously or subcutaneously. Intramuscular injection is contraindicated because of the likelihood of hematoma formation.
- Since heparin’s anticoagulant effects occur through a simple binding reaction with antithrombin III and clotting factors, its onset of action is dictated primarily by its rate of appearance in the plasma. Thus, when rapid anticoagulation is required, therapy is initiated with a bolus IV injection followed by a continuous IV infusion. When a slower onset is sufficient, i.e., prophylaxis prior to surgery, a subcutaneous injection of heparin or LMWH is typically used.
Heparin: Continuous Intravenous Infusion:
Adults: Initially a bolus dose is injected into the tubing after the infusion is started, then a continuous infusion rate is maintained (infusion pump). The rate is subsequently adjusted according to the results of the aPTT performed 4 hours later. Advantages: immediate onset of anticoagulant effect, stable blood concentrations. Disadvantages: infusion pump required for long term therapy, may cause hypervolemia, patient discomfort, pump must be carefully monitored.
heparin: Intermittent Intravenous: (not recommended)
Adults: 5,000 units initially, followed by 5,000 to 10,000 units every four to six hours. Advantages: avoids fluid infusion. Disadvantages: greater variation in blood concentrations and requires frequent laboratory tests to regulate the dose.
Subcutaneous low dose prophylaxis (“minidose”) of heparin
5,000 units two hours before surgery and every 8 or 12 hours thereafter until the patient is discharged or is fully ambulatory. For adjusted dose prophylaxis or treatment, dosage is guided by the aPTT (usually 1.5 to 2.5 times control). For full dose effects give 10,000 - 12,000 units every eight hours or 15,000 - 17,500 units every 12 hours. The drug should be injected in the smallest volume possible at different sites around the iliac crest, over the lower abdomen, or thigh. A small needle should be used to prevent massive hematoma.
Extracorpeal Uses: Heparin
Heparin Sodium Lock Solution (Hep-Lock) Heparin is used to flush out IV lines, etc. Sometimes tubes and pipettes used in blood work are “heparinized” to prevent coagulation. These solutions are not for therapeutic use.
** Monitoring heparin therapy
aPTT = 1.5 to 2.5 times control.
Termination of heparin
up to 50% of dose is excreted unchanged in urine remainder metabolized in liver to a weakly active derivative. Elimination half-life is dose-dependent principally because UFH binds to plasma proteins and endothelial cells in a saturable process. This binding also limits the bioavailability of UFH after subcutaneous injection.
Heparin toxicity
Hemorrhage from inadvertent overdose, bleeding from undiagnosed disease site (ulcer, carcinoma).
- Hematoma formation at surgical site or from SC or IM injection
- Heparin-induced thrombocytopenia (HIT). Heparin induces transient thrombocytopenia in as many as 25% of patients but this usually resolves spontaneously. However, in approximately 5% of patients a severe thrombocytopenia can evolve days after the initiation of therapy. This heparin-induced thrombocytopenia or HIT syndrome is due to the formation of antibodies directed against the heparin- platelet factor 4 complexes. These antigen-antibody complexes bind to Fc receptors on adjacent platelets causing aggregation, platelet activation and paradoxical thrombosis. HIT with thrombosis can be treated with direct thrombin inhibitors (see section J below).
- Less common side effects include acute hypersensitivity, alopecia, platelet aggregation, osteoporosis (1 year therapy), and priapism.
Heparin contraindications
active bleeding, perform blood coag tests and look for occult bleeding
severe hypertension/ vascular aneurysm, hemophilia, thrombocytopenia, intracranial hemorrhage, active tuberculosis, ulcerative lesions of the GI tract, threatened abortion, or visceral carcinoma. Heparin should be withheld during and after surgery of the brain, eye, or spinal cord, and should not be given to patients undergoing lumbar puncture or regional anesthetic block. The drug should be used only where clearly indicated in pregnant women, despite its apparent lack of transfer across the placenta.
Heparin indications
Deep venous thrombosis and pulmonary embolism: treatment and prophylaxis.
2. Extra corporeal circulation (hemodialysis and heart-lung machine); due to in vitro effects
3. Prophylaxis of postoperative and recumbency thrombosis
4. Myocardial infarction and unstable angina
Lessen incidence of secondary peripheral venous thrombosis and pulmonary embolism.
Recommended treatment during acute MI is: aspirin therapy immediately (+O2, nitroglycerin, and morphine), followed by thrombolytic therapy (if percutaneous coronary intervention (PCI) cannot be conducted), followed by heparin IV. Heparin is usually contraindicated if PCI is anticipated.
5. Disseminated intravascular coagulation (DIC)
Treatment of Heparin Overdose:
Protamine Sulfate
- Immediate withdrawal of heparin if bleeding complications occur.
- Protamine sulfate: is a strongly basic protein administered IV that binds and inactivates heparin because of its strong positive charge. Protamine may cause transient hypotension if given too rapidly. This drug must be used cautiously to avoid thrombotic complications. Occasionally, anaphylactic reactions occur. Protamine sulfate is not capable of reversing the effects of warfarin.
LMWH vs heparin
smaller fragments (2000 to 8000 daltons) extracted from unfractionated heparin. • The preparations differ from unfractionated heparin in having a greater ratio of anti-factor Xa to antithrombin (IIa) activity and less effect on platelet activity. LMWH preparations have been developed with the goal of decreasing bleeding episodes while still retaining anticoagulant activity, especially for the prevention of deep venous thrombosis (DVT) in surgical patients. • Other favorable properties of LMWHs over standard heparin include greater bioavailability after subcutaneous administration, a longer duration of anti-factor Xa activity that allows for less frequent dosing intervals, linear pharmacokinetics, possibly fewer side effects, i.e., less incidence of HIT syndrome, and lack of required laboratory monitoring (i.e., no aPTT is required).
Indications and Usage: LMWH
Enoxaparin is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism:
•In patients undergoing abdominal surgery who are at risk for thromboembolic complications.
•In patients undergoing hip replacement surgery, during and following hospitalization.
•In patients undergoing knee replacement surgery.
•In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.
Enoxaparin sodium injection is indicated for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin.
Enoxaparin also is indicated for:
• The inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium.
• The outpatient treatment of acute deep vein thrombosis without pulmonary embolism when administered in conjunction with warfarin sodium.
Current clinical trials suggest:
• that bleeding complications can still occur with LMW heparin therapy and some cases of thrombocytopenia have been reported.
• LMWH are contraindicated during spinal / epidural anesthesia or spinal puncture because of the increased risk of spinal hematomas.
• Home therapy is available for selected patients. Doses are determined based on body weight and pre-filled syringes are prescribed for the patient’s use at home after suitable training.
