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medications for thromboembolic disorders
Terms in this set (31)
Pharmacologic Approaches for thromboembolic Disorders - general
Drugs that interfere with platelet aggregation =
Drugs that interfering with the clotting cascade =
Drugs that lyse thrombi =
Pharmacologic Approaches for thromboembolic Disorders
Antiplatelet Agents / Anticoagulants
: Suppress thrombosis (thrombus formation). Do NOT "dissolve" clots.
-Are used to
prevent or manage
conditions such as:
--- DVT (due to prolonged immobility, orthopedic surgery, trauma)
--- Atrial fibrillation sequelae (increases risk of stroke)
---Hypercoagulable states (e.g. Factor V Leiden mutation)
--- Supplement post-thrombolytic therapy or stent placement
: Lyse an existing thrombus.
-Are used to
conditions such as:
--- ST-elevation Myocardial Infarction (STEMI)
--- Ischemic Stroke
--- Pulmonary Embolism
Mechanism of Platelet Aggregation
Mechanism of platelet aggregation and actions of antiplatelet drugs. Activation of the GP IIb/IIIa receptor permits binding of fibrinogen, which causes aggregation by forming cross-links between platelets. After aggregation occurs, the platelet plug is reinforced with fibrin (not shown). (ADP, adenosine diphosphate; GP IIb/IIIa, glycoprotein IIb/IIIa receptor; PAF, platelet activation factorTXA2, thromboxane A2.)
Platelets adhere to exposed collagen/vWF through integrins such as Glycoprotein Ib
Integrin engagement produces signals that activate the platelet
ADP and thromboxane A2 release provides a second activation wave by activating nearby platelets.
Activated Glycoprotein IIb/IIIa binds to fibrinogen, aggregating platelets.
The P2Y12 receptor is the predominant ADP receptor involved in the ADP-stimulated activation of the glycoprotein IIb/IIIa receptor.
MoA of aspirin
Irreversible inhibitor of COX-1 function for the life of the platelet
Platelets do not have a nucleus so they cannot make new COX -1 (or any protein)
For the life of the platelet (7-10 days) COX-1 cannot function. No COX-1 -> no TxA2 produced via AA Cascade
Aspirin blocks production of TxA2
Platelets are complex cell fragments containing numerous chemical mediators that are released when platelets are activated. Platelets display a variety of cell surface receptors that mediate both adhesion to exposed subendothelium and aggregation with other platelets. ADP, Adenosine diphosphate; Epi, epinephrine; TxA2, thromboxane A2; vWF, von Willebrand factor.
Platelets secrete pro-clotting substances - many of which they also have receptors for.
Platelets have receptors for pro-clotting signals.
Indication - Primary and secondary prevention of MI, ischemic stroke, TIA, angina. Acute MI.
Mechanism - antiplatelet; irreversibly inhibits COX (COX-1 > COX-2)
(stop aspirin 7-10 days before surgery), GI distress and/or bleed,
, tinnitus, hypersensitivity reactions (including anaphylaxis),
Do NOT give to children under age 18
-warfarin (increases warfarin levels)
-anticoagulants (increases bleeding risk)
-glucocorticoids (increases risk of gastric ulceration)
-alcohol (increases risk of gastric bleed)
-ACE inhibitors and ARBS (increases risk of kidney injury)
Why use low dose Aspirin for prevention of MI and stroke?
Wouldn't regular/high dose Aspirin inhibit the platelets AND provide anti-inflammatory benefits?
-Inhibition of prostacyclin (PGI2) occurs when COX-2 is blocked.
-PGI2 inhibits platelets and vasodilates. Inhibiting PGI2 would partially offset the benefits of aspirin therapy....so we want to keep PGI2 at the same time we inhibit TxA2 .
-Low-dose aspirin is able to inhibit TxA2 at doses lower than those required to inhibit PGI2. So if we keep the aspirin low-dose, we minimize the inhibition of PGI2 , while still inhibiting TxA2 .
-Higher doses of aspirin inhibit platelets just like low dose aspirin
-BUT, higher doses of aspirin also inhibit endothelial generation of prostacyclin (PGI2) via COX-2
-Loss of PGI2 removes one restraint on platelets, reducing the benefit of platelet COX-1 inhibition.
we want to stop a clot from forming - enough to block the bad one, not enough to block the good one as well
Aspirin In Acute MI
325 mg of non-enteric coated aspirin should be
if an MI is strongly suspected.
-Pt teaching point!
-Avoid aspirin if stroke is suspected, as it could be a hemorrhagic stroke, and not ischemic
-enteric coated can mess with absorption
325 mg loading dose- large enough to inhibit a lot of platelets, which are rapidly aggregating.
-COX-2 inhibition will inhibit PGI2, but at this moment, our goal is to minimize the size of the clot that is likely still acutely evolving and growing
; ADP receptor antagonist
Indication - ACS, prevent stroke, MI and death in patients with recent MI/stroke/PAD
MoA - antiplatelet; irreversible ADP receptor antagonist -> inhibits platelet aggregation for the life of the platelet
CYP2C19 converts the prodrug to its active form
Adverse effects - bleeding, dyspepsia, abdominal pain, diarrhea, rash
Interactions - antiplatelet and anticoagulant agents, some
9*, which converts clopidogrel to active form. Use an alternative PPI.
Some people have an allele of the gene that codes for CYP2C19 that makes them
of clopidogrel -> gain little benefits
; Gp IIb/IIIa inhibitor
Indication - ACS managed medically or with PCI
Mechanism - antiplatelet; Glycoprotein IIb/IIIa receptor inhibitor -> no receptor for fibrinogen -> platelet aggregation inhibited.
, hypotension, thrombocytopenia (rare immune reaction to drug)
Interactions - with antiplatelet drugs, heparin, thrombolytics, aspirin and other NSAIDs
-major surgery in prior 6 weeks
-bleeding or stroke within previous 30 days
-history of hemorrhagic stroke
High Alert Medications
Institute for Safe Medication Practices (ISMP) high-alert medication drug class in acute care and long-term care settings.
"High-alert medications are drugs that bear a heightened risk of causing significant patient harm when used in error. Although mistakes may or may not be more common with these drugs, the
consequences of an error are clearly more devastating to patients
-48% of hospital medication errors involve anticoagulants.
-In patients >65 years old, anticoagulants are most commonly implicated med in ED visits due to adverse drug event (ADE).
Class: Anticoagulant; Vitamin K Antagonist
Indication: prevention of thrombosis associated with DVT/PE, prosthetic valves, atrial fibrillation. Tx of DVT/PE
Mechanism: anticoagulant; prevents active Vitamin K regeneration (vitamin K epoxide reductase, VKORC1), which reduces levels and functionality of vitamin-K-dependent clotting factors (II, VII, IX, X)
- any drug interaction that reduces protein binding increases free warfarin -> inc risk of bleeding
Monitor PT/INR. Goal: INR 2-3 for most indications.
-Inr 1 is normal - we want them to bleed more easily than normal
Contraindicated in pregnancy (formerly "Category X")
-Teratogenic, intrauterine growth restriction, fetal death.
Interactions - antiplatelet and anticoagulant agents (combined effects), vit K, metabolizing enzyme inhibitors and inducers
Many, many drug interactions, including many antibiotics
Antidote: Vitamin K, 4F-PCC
(4 factor prothrombin complex concentrate; Factors II, VII, IX, X).
Warfarin prevents formation of the activated form of Vitamin K inhibition of Vitamin K-dependent clotting Factors
Warfarin inhibits VKORC1, preventing regeneration of active form of Vitamin K
- look at slide
genes and warfarin
Response to warfarin is affected by variant alleles of
that code for: (1) VKORC1 (the drug's target), and (2) CYP2C9, the main metabolizing enzyme of warfarin
Depending on the person's genotype, there can be a 22-76% dose reduction required, as compared to a person with wild-type alleles.
Warfarin: Patient & Family Teaching
Get INR checked at frequency recommended by healthcare provider.
Avoid other drugs that can increase bleeding risk, including OTC NSAIDs, aspirin
Tell other providers, including dentist, that you are taking warfarin.
Safety precautions to avoid falls, cuts, bruises.
Do not need to avoid all foods containing Vitamin K, but maintain a consistent intake of these foods (bc dosing)
Medical Alert bracelet.
Patients with cognitive dysfunction should not have free access to multiple tabs of warfarin
Heparin and enoxaparin Mechanism of Action
Heparin and enoxaparin* increase activity of antithrombin, which inhibits thrombin (Factor IIa - crosslinking of fibrin) and Factor Xa (common pathway)
Antithrombin blocks both thrombin and Factor Xa. Heparin binds directly to antithrombin and thrombin. Heparin does not bind directly to Factor Xa
*Enoxaparin preferentially inactivates Factor Xa and has much less effect on thrombin. Heparin inactivates both factors.
Heparin (aka Unfractionated Heparin)
Class: Anticoagulant; unfractionated heparin (UFH)
Indic: treatment/prevention of thrombosis (MI, DVT, PE, stroke, immobility), prevention of post-op venous thrombosis, extracorporeal circulation (open heart surgery), dialysis
MoA: anticoagulant; inc. antithrombin activity 1000x (antithrombin blocks thrombin and Factor Xa)
doses in UNITs
Adverse Effects -
, heparin‐induced thrombocytopenia (HIT);
Interactions - antiplatelet, anticoagulant medications
Caution in patients with bleeding risk or spinal/epidural catheter (risk of hematoma -> can cause permanent neurological injury). Caution in pregnancy (but not specifically contraindicated).
Antidote: Protamine sulfate
Unfractionated Heparin (UFH)
Heparin binds antithrombin:
->Antithrombin binds and inactivates Xa (Xa does not have to directly come into physical contact with heparin molecule)
->Antithrombin binds and inactivates IIa/thrombin but IIa must also come into direct physical contact with heparin to be inactivated
Heparin-induced thrombocytopenia (HIT)
Prothrombotic disorder caused by formation of antibodies to complexes of platelet factor 4 (PF4) and heparin.
Antibodies bind to the PF4-heparin complexes on quiescent platelet surface and induce platelet activation.
-> increase release and surface expression of PF4, creating a positive feedback loop in which further release of PF4 promotes further platelet activation
Platelet activation -> release of procoagulant platelet microparticles,
, platelet consumption, and eventual thrombocytopenia. Greatly increased generation of thrombin, activation of inflammatory cells, and endothelial injury and activation follow.
Can cause both venous and arterial thromboses
, with devastating results. Extremities often affected.
Patients who have had a previous episode of HIT are at high risk for another episode; heparin should be avoided in the future unless there is no alternative.
Both heparin and enoxaparin are derived from pigs (intestinal mucosa)
Concerns among certain patient populations - jews, muslims, vegans
Ethical obligations as nurses - discuss so you don't violate informed consent, autonomy, let them talk to religious leaders
Enoxaparin (Lovenox®) (Low Molecular Weight Heparin)
; low molecular weight heparin (LMWH)
Indication: treatment and prevention of DVT, ischemic complications of acute MI, post-thrombolysis
Mechanism: anticoagulant; low-molecular weight heparin - inc antithrombin activity
-Preferentially inactivates Factor Xa, much less effect on thrombin (IIa), unlike heparin which works on both thrombin and Factor Xa. This is due to the shorter molecule length, which does not permit binding to thrombin in most cases.
, heparin‐induced thrombocytopenia (HIT) (less risk than heparin, but not zero risk), ecchymosis, "lovenox belly" rainbow spots
Interactions - antiplatelet agents, other anticoagulants
Caution in patients with bleeding risk, spinal/epidural catheter for same reasons as heparin.
Monitoring: Not usually monitored w/labs, but you may see a Low Molecular Weight Heparin assay ordered occasionally, esp. for pts w/low GFR
Antidote: Protamine sulfate
-anti-Factor Xa activity is only partially neutralized (≈60%) with protamine sulfate
Low Molecular-Weight Heparin (LMWH)
LMWH (enoxaparin) is a shorter molecule than UFH (heparin). It frequently is not long enough to provide a binding site for thrombin, unlike UFH. As a result, it is much better at inactivating Factor Xa, and has much less effect on thrombin (IIa). Factor Xa does not have to come into direct physical contact with enoxaparin, similar to heparin.
Dabigatran Mechanism of Action
Dabigatran directly inhibits thrombin, preventing conversion of fibrinogen to fibrin; prevents activation of Factor XIII, which normally causes fibrin crosslinking.
Dabigatran Etexilate (Pradaxa®)
; direct thrombin inhibitor
Indication: prevention of systemic embolism and stroke in patients with atrial fibrillation (A-fib); DVT/PE treatment and prophylaxis of recurrent DVT/PE, post-op prophylaxis of thromboembolism
MoA - anticoagulant; reversible direct thrombin inhibitor. Binds to free thrombin and thrombin bound to clots.
- converted to active metabolite (dabigatran) in
plasma, gut and liver
. Converted via enzymes known as
, not CYP
, including spinal/epidural hematoma,
-inc risk of thrombotic event if drug is discontinued prematurely.
Interaction - P-glycoprotein inhibitors (e.g., ketoconazole, verapamil, carvedilol) or inducers (e.g., rifampin), other anticoagulants.
if active bleeding or mechanical prosthetic heart valve,
eGFR ≤ 30
Antidote/reversal agent: idarucizumab (Praxbind®)
P-Glycoprotein Efflux Pumps - dabigatran
P-glycoproteins pump drugs out of cells ("efflux pump"); decreases drug absorption.
In this case, P-glycoprotein pumps Dabigatran Etexilate back into the intestine =>
Dabigatran absorption and serum levels, inducers of P-glycoprotein decrease Dabigatran absorption and serum levels
Dabigatran Etexilate antidote/reversal agent: idarucizumab (Praxbind®)*
Monoclonal antibody - very expensive!!!
Patient teaching: Keep medication in original manufacturer bottle with dessicant (dry) cap, or in original blister pack. (Med. is unstable when exposed to moisture.) Take capsule intact; do not chew or crush.
Real life story from Institute for Safe Medication Practices:
A patient at a nursing home came to the hospital. He was vomiting blood and needed to be admitted. It is believed that some nurses at the care facility may have been opening the Pradaxa capsules and sprinkling the contents on the patient's food because he had a hard time swallowing the medicine.
Rivaroxaban Mechanism of Action
Rivaroxaban directly inhibits Factor Xa, in the final common pathway of the coagulation cascade.
Class: Anticoagulant; Factor Xa inhibitor
Indication - prevention/treatment of DVT/PE; prevention of recurrent DVT/PE; prevention of stroke in A-fib, post-op DVT prevention
Mechanism - anticoagulant; Factor Xa inhibitor
including spinal/epidural hematoma; paradoxical increased risk of thrombotic stroke
Interactions - other anticoagulants; P‐glycoprotein/ CYP3A4/5 inducers (e.g., rifampin, carbamazepine, St. John's Wort) and inhibitors (e.g., ketoconazole, ritonavir, carvedilol, verapamil)
Contraindicated if active bleeding, eGFR ≤ 30.
-andexanet alfa (Andexxa®), a Factor Xa "decoy protein"
-binds and inhibits both rivaoxaban and apixaban, another Factor Xa inhibitor
Thrombolytics ("Clot Busters")
Alteplase (tPA - tissue plasminogen activator) activates plasminogen which activates plasmin, an enzyme that digests the fibrin network of clots. It is identical to endogenous tPA.
Fibrinolysis. Plasmin, activated from plasminogen, enzymatically cleaves fibrin proteins in the clot. This results in fibrin split products, which can be measured by laboratory tests.
Alteplase (tPA) acts exactly the way endogenous plasminogen activators would act: plasmin, derived from plasminogen, enzymatically degrades clots by digesting fibrin (lyses clots) and degrading fibrinogen (Factor I) and other clotting factors.
Alteplase (tPA) (Activase®)
Indic: Acute MI, Pulmonary embolism, Ischemic stroke. Most effective if given < 30 min of arrival
MoA: thrombolytic/fibrinolytic. Activation of fibrin-bound plasminogen. Identical to endogenous human tPA.
Adverse Effects: bleeding.
Contraindicated if prior hemorrhagic stroke, ischemic stroke within last 3 months, intracranial neoplasm, serious head trauma internal bleeding, aortic dissection.
Caution with uncontrolled HTN, remote stroke (> 3 months), recent trauma, post surgery (major, less than 3 weeks ago), active PUD, pregnancy, current use of anticoagulants
Interaction with antiplatelet / anticoagulant agents
Goal is to reduce the pain of exertional angina, primarily by decreasing cardiac oxygen demand. Remember, during exertion, the only way the heart can increase blood flow and subsequent oxygen supply is to dilate coronary arteries.
Sufficient dilation may not be possible in people with CAD.
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