Download Chapter 48 Antidysrhythmic Drugs

Anticoagulant, Antiplatelet,
and Thrombolytic Drugs
A few terms to know…
 Coagulation- the physiologic process by which the blood clots to form solid
masses, or clots. (Over 30 types of cells and substances in blood affect
clotting.)
 A blood clot is a thick mass of coagulated blood, platelets and other
materials stuck together
 A thrombus (pl, thrombi) is an intravascular clot. (A thrombus can break into
smaller pieces, dislodge from the location where it was initially formed.)
 An embolus is a blood clot, piece/globule of fatty deposit, or other object
that is carried through the bloodstream.
 An embolism refers to the obstruction of a blood vessel by a foreign
substance or a blood clot that travels through the bloodstream, lodges in a
smaller blood vessel, and plugs it.
 Substances that can cause embolisms include: blood clots; piece/
globule of fatty deposit; clumps of bacteria, ‘vegetation’ or ‘debris’ on a heart
valve; amniotic fluid; air bubble, chemicals and drugs (mainly illegal ones).
 Blood clots are the most common cause of embolisms.
Formation of intravascular clots
► Protective when injury to blood vessel would lead to hemorrhage
and blood loss
● Insults to blood vessels occur in normal physiology
► Problematic, dangerous and even life-threatening, for example:
● Certain hypercoaguable states
‒ Genetic; iatrogenic; diseases such as leukemia
● Prosthetics
‒ artificial heart valves
● Impaired mobility
‒ Post-operative bed-rest; long airplane flights
● Emergency situations
‒ Ischemic stroke; myocardial infarction; massive pulmonary embolus
● Other
►Therefore, drugs are commonly used to reduce risk of clot, or to
treat a clot that has formed
Physiology and Pathophysiology of Coagulation
● Thrombosis‒ may result in severe consequences, due to
reduction or cessation of blood flow to a tissue by the thrombus
itself, or by rupture and release of thrombi
● Arterial thrombosis• Platelet adhesion (often ruptured atherosclerotic plaque)
• Release of ADP & TXA2
• Causes decreased/ absent perfusion distally
-medical emergency
• Depending on source of embolus, the clot may embolise to
lower extremities, brain, heart, kidney, spleen, bowel
● Venous thrombosis
• Stagnation of blood in lower extremities
– Fibrin formation
• Typically embolise to right side of heart then lungs (safety net)
• Paradoxical emboli (cross from venous circulation through a
septal defect between the right and left sides of the heart,
thereby entering the arterial circulation)
Complications of intravascular clots: short and long-term
Arterial vs venous clots
Ischemic cerebrovascular accident (CVA, stroke, “brain attack”)
and Myocardial Infarct (MI, “heart attack”)
are two of the most feared events
Ex: Arterial blockage in lower extremities
Ex: Venous blockage in lower extremities
Ex: Venous blockage in lower extremities
Lower extremity DVT can embolise to the lungs
Animations of hemostasis (blood coagulation cascade)
Hemostasis, Coagulation and Fibrinolysis
https://www.youtube.com/watch?v=9QVTHDM90io
The Coagulation Cascade
http://www.allaboutbleeding.com/includes/videos/CoagCascade.mp4
Clot formation begins with tissue injury, which then activates platelets.
When activated, platelets induce fibrin strand formation
from platelet to platelet, thereby forming a fibrin mesh (clot)
Figure 52-1B Mechanism of platelet aggregation and actions of antiplatelet drugs.
Physiology of clot formation:
•Stage One of Hemostasis: Formation of a “platelet plug”
– Injury: Endothelial cells that line the blood vessel wall, and the
sub-endothelial tissues, get injured
» Components in the blood (eg platelets, clotting factors)
are exposed to molecules from the injured endothelial cells
and sub-endothelial tissues (eg tissue factor, collagen)
» Note: Clotting factors, platelets and other molecules are
inactive under normal conditions, but become activated
sequentially
– Platelets adhere to damaged tissue, become activated,
amplify the clotting cascade, and aggregate at the site of
injury
– Vasoconstriction triggered by Injury to the blood vessel wall:
smooth muscles in blood vessel wall immediately vasoconstrict
the vessel, which reduces blood loss from the ruptured vessel
Physiology of clot formation, cont’d:
•Stage Two of Hemostasis:
Coagulation leads to fibrin formation via
‒ Intrinsic pathway (aka contact activation pathway, turned on
by contact with sub-endothelial collagen)
‒ Extrinsic pathway (aka tissue factor pathway, turned on by
release of tissue factor from damaged cells)
‒ The intrinsic and extrinsic pathways have the common step of
activating Factor X: this begins the “common pathway”.
o Activation of factor X
o Conversion of prothrombin to thrombin
o Production of fibrin
o Then, later, clot contraction
• Hemostasis is kept under control by ANTITHROMBIN
• Physiologic dissolution of clots (fibrinolysis) after tissue
repair.
•Release of Tissue Plasminogen Activator (t-PA) converts
plasminogen to PLASMIN
INJURY
Exposed collagen
Damaged tissue
Thrombolytics
Lehne, Figure 52-2, page 596
Drugs used to treat
Thromboembolic Disorders
Three major classifications of drugs:
• Anticoagulants:
−Suppress the coagulation cascade
−Heparin, warfarin
• Antiplatelets:
−Inhibit platelet aggregation
−Aspirin, clopidogrel
• Thrombolytics:
−Promote lysis of fibrin strands, causing
dissolution of thrombi
−tissue plasminogen activator ie t-PA (alteplase)
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• Reduce the formation of fibrin
• Two mechanisms of action
• Inhibit the synthesis of clotting factors
• Inhibit the activity of clotting factors
HEPARIN
AND HEPARIN DERIVATIVES
Heparin (unfractionated, UFH)
• Heparin (unfractionated) is not a single molecule, but a mixture
of long polysaccharide chains, with molecular weights that vary
from 3000 to 30,000 (units? kD?)
– Active region is a unique penta-saccharide (five carbon sugar)
– used for decades for prevention & treatment of thrombosis
– Highly polar, cannot readily cross membranes
– Mechanism: suppresses coagulation by helping antithrombin to
inactivate clotting factors, primarily thrombin (factor II) & factor
Xa, and thereby suppresses formation of fibrin
• Particularly effective for prophylaxis of venous thromboses
– BUT: variable anticoagulant effects, pharmacological properties,
limited bioavailability, and highly variable anticoagulant response
– Very rapid-acting anticoagulant (onset within minutes of IV
administration)
– Half-life only 1.5 hours, unless hepatic or renal disease
– Hepatic metabolism, renal excretion
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Heparin (Unfractionated, UFH)
• Therapeutic uses
– Preferred anticoagulant during pregnancy and when rapid
anticoagulation is required
• Does not enter breast milk
– Pulmonary embolism (PE)
– Ischemic stroke, evolving
(t-PA may be preferred if given within 2 hours of symptoms)
– Massive deep vein thrombosis (DVT)
– For anticoagulation during extracorporeal procedures when
blood flows through machine
• Open heart surgery
• Renal dialysis
– Low-dose therapy postoperatively (DVT prophy)
– Disseminated intravascular coagulation (DIC)
– Adjunct to thrombolytic therapy (eg MI)
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Heparin (Unfractionated, UFH)
• Intensive lab monitoring required
– Activated partial thromboplastin time (aPTT) (p 601)
– Follow protocol
• Draw blood Q 4-6 hours for continuous infusion.
• Adjust dose based on lab results
• During short-term, low-dose prophylactic tx, labs aren’t usually required
• Units, Route & preparations
• Dosed in units
• Administered only by IV or subcut
• IV-
– Most commonly, a bolus dose (based on weight) is administered,
followed by continuous infusion (based on weight. Lab is
checked after 4 – 6 hours to titrate infusion rate up or down.
– Or intermittent infusion (not common)
• Deep subcutaneous (subQ) (BID or TID)
• Several formulations and concentrations available
– Dilute vs concentrated; single dose vs multi-dose vials
– Read labels carefully.
– Check IV bag and infusion pump carefully.
• Antidote for overdose: Protamine sulfate
Heparin (Unfractionated, UFH)
• Adverse effects- reduce risk of bleeding by screening pts for
risk factors, monitor closely and avoid antiplatelet drugs
– Hemorrhage
– Heparin-induced thrombocytopenia (HIT)
• antibodies form against heparin-platelet protein complexes
• Increases thrombotic events
• Uses up all the platelets (↓platelet level)
• Is an absolute contraindication to giving heparin again
– Hypersensitivity reactions
commercial preparations derived from animal sources
• Contraindicated
– Thrombocytopenia
– Uncontrollable bleeding
– During and immediately after surgery of the eye, brain, or
spinal cord
Nursing Implications r/t Monitoring for,
and Teaching, S/S of Bleeding
•
•
•
•
•
•
•
↓BP, ↑Heart Rate
Headache, faintness
Petechiae, bruises, hematoma
Red or black stools
Cloudy or discolored urine
Pelvic pain (possible ovarian hemorrhage)
Lumbar pain (possible adrenal hemorrhage)
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Nursing Implications r/t Minimizing the Risk of Bleedingteach to patient/family prn
• Screen for risk factors
• Follow requirements for therapeutic drug monitoring
• Beware drug or food interactions. Monitor blood levels
carefully any time a new drug is added, or a current drug is
discontinued from the drug regimen.
• Minimize physical manipulation of the patient
• Minimize invasive procedures (eg foley catheter)
• Avoid subcut and IM injections
• Minimize concurrent use of anticoagulants
– for example, heparin, warfarin, dabigatran)
• Minimize concurrent use of antiplatelet drugs
– for example, aspirin, clopidogrel
• Use in caution in those with CPR or surgery within previous 3
weeks
• Avoid noncompressable vascular puncture sites
• Wear identification for emergency personnel
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Question- which lab is used to monitor
effects of heparin?
A patient is receiving an intravenous infusion of
heparin to treat a pulmonary embolism. What
laboratory value will the nurse monitor to evaluate
treatment with this medication?
A.
B.
C.
D.
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
Platelet count
Hemoglobin and hematocrit
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Question: antidote for heparin overdose?
What is the antidote for heparin?
A.
B.
C.
D.
Ferrous sulfate
Atropine sulfate
Protamine sulfate
Magnesium sulfate
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Low-Molecular-Weight Heparins
• Heparin preparations composed of molecules that are shorter
than those found in unfractionated heparin
• LMWH as effective as UFH
• Mechanism: inactivates Factor Xa
– not effective to inactivate thrombin
• Administered subcut
• Dosage based on body weight (fixed dose)
 Advantages:
fixed dose, no lab, highly predictable plasma levels
 Cost: considerably more expensive
 But, does not require labs/ monitoring; can be given at home
 Pharmacokinetics

Higher bioavailability

Longer half-life- permits once or twice a day dosing
• Antidote for toxicity: Protamine sulfate
•
Low-Molecular-Weight Heparins
Adverse effects
– Bleeding (but less than with unfractionated heparin)
– Heparin-induced thrombocytopenia (HIT)
– Severe neurologic injury for patients undergoing spinal
puncture or spinal epidural anesthesia
• Therapeutic uses
– First-line therapy for prevention and tx of DVT
– Prevention of DVT following surgery
• abdomen; hip or knee replacement
– Off label use for DVT prophylaxis
• in multi-trauma, or spinal surgery
– Prevention of ischemic complications in pts with unstable
angina, non Q-wave MI, and ST-elevation MI (STEMI)
Three on market:
 Enoxaparin (Lovenox)- used in >80% of hospitals
 Dalteparin (Fragmin)
 Tinzaparin (Innohep)
All anticoagulants
• Pose a risk of spinal or epidural hematoma
in patients undergoing spinal puncture or
spinal/ epidural anesthesia
• Pressure of hematoma on spinal cord can
result in prolonged or permanent paralysis
• See Lehne text, p 599
RECOMMENDATION: Health care professionals and institutions
involved in performing spinal/epidural anesthesia or spinal punctures
should determine, as part of a pre-procedure checklist, whether a
patient is receiving anticoagulants and identify the appropriate timing of
enoxaparin dosing in relation to catheter placement or removal. To
reduce the potential risk of bleeding, consider both the dose and the
elimination half-life of the anticoagulant:
For enoxaparin, placement or removal of a spinal catheter should be
delayed for at least 12 hours after administration of prophylactic doses
such as those used for prevention of deep vein thrombosis. Longer
delays (24 hours) are appropriate to consider for patients receiving
higher therapeutic doses of enoxaparin (1 mg/kg twice daily or 1.5
mg/kg once daily).
A postprocedure dose of enoxaparin should usually be given no sooner
than 4 hours after catheter removal.
In all cases, a benefit-risk assessment should consider both the risk for
thrombosis and the risk for bleeding in the context of the procedure and
patient risk factors.
Medwatch 11/2013
WARFARIN
Warfarin, the first oral anticoagulant
• Originally discovered when a farmer observed that his cattle began
bleeding after ingesting spoiled clover silage
– Deemed too risky for humans  used as rat poison
– A failed suicide attempt with large dose brought renewed clinical
interest
• Used to prevent thrombosis
• Mechanism: suppresses coagulation by decreasing production of four
clotting factors (VII, IX, X and prothrombin, all of which are dependent
on vitamin K)
• PK: only administered orally, well absorbed; 99% bound to albumin;
unbound warfarin readily crosses into placenta and breast milk;
hepatic metabolism by CYP2C9; metabolites excreted in urine & feces
• Clinical considerations
–Initial onset 6 – 12 hours after first dose; peak effect takes several days
to develop. (Not useful in emergencies)
–Effect persists 2 – 5 days after discontinuing
–Drug therapy typically initiated with heparin (which has immediate
onset) until warfarin is at therapeutic levels
–Warfarin may need to be temporarily DC’d for elective surgery (Heparin
is re-instituted during interim until safe to go back on warfarin)
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Warfarin, the first oral anticoagulant
• Lab monitoring ESSENTIAL!
– Never does a person “not need” monitoring, although frequency
of labs are somewhat individualized
– Prothrombin time (PT)/ International normalized ratio (INR)
‒ Normal PT/INR is 1.0
‒ Patient’s “Goal PT/INR” depends on condition being treated
‒ Longest reasonable amount of time between labs 2 – 4 weeks
‒ Patients titrate daily dose of warfarin based on PT/INR values
• Antidote Vitamin K1 (phytonadione)
•
•
oral preferred (IV has risk of allergy or anaphylaxis)
Useful in emergencies (eg sudden trauma)
• Therapeutic use: long-term prophylaxis of thrombosis
• Prevention of venous thrombosis and associated risk of
pulmonary embolism
• Prevention of thromboembolism
– Eg in patients with prosthetic heart valves
• Prevention of thrombosis in patients with atrial fibrillation
• Reduce recurrent Transient Ischemic Attacks and MI
Warfarin, the first oral anticoagulant
• Adverse effects
– Bleeding
– Hemorrhage
– Fetal hemorrhage and teratogenesis
• Pregnancy Category X
• Contraindicated during lactation
– Other adverse effects
• Patient Teaching
– S/S of bleeding; monitoring plan- schedule of labs; drug and
food interactions; must tell all providers of all drugs; wear
“MedicAlert”-type identification; stop warfarin (use another
method) until after an elective surgery
– Take at same time every day
– Warfarin has perhaps the most drug or food interactions of
any medication!
Warfarin, the first oral anticoagulant
• Drug interactions (p 606- 607)
– Warfarin has perhaps the most drug and food interactions of
any medication!
– Worrisome due to increased bleeding or loss of protection
– Drugs that increase anticoagulant effects
• Heparin, aspirin, acetaminophen
– Drugs that promote bleeding
• Drugs that compete for binding with plasma proteins
• Drugs that induce or inhibit the drug-metabolizing enzymes
(CYP2C9)
– Drugs that decrease anticoagulant effects
• Contraindicated: very large list (p 607)
• severe thrombocytopenia and others at high risk of bleeding
• Patients undergoing a variety of procedures or surgeries
• Liver disease, alcoholism- conditions that can disrupt
production of clotting factors
• Pregnancy and lactation
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Warfarin, the first oral anticoagulant
• Teach pt to ingest the same amount of dietary
Vitamin K each day
• Dietary vitamin K: Mayonnaise, canola oil,
soybean oil, and green leafy vegetables
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Question: warfarin and drug interactions
Which patient does the nurse identify as most likely
needing an increased dose of warfarin [Coumadin] to
have the same anticoagulant effect?
A.Patient taking acetaminophen [Tylenol] for back pain
B.Patient taking cimetidine [Tagamet] to prevent gastric
ulcers
C.Patient taking oral contraceptives to prevent
pregnancy
D.Patient taking prednisone [Deltasone] for rheumatoid
arthritis
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HEPARIN
VS.
WARFARIN
Comparison between
Heparin & Warfarin
MOA
Route
Onset
Heparin
Warfarin
Inactivates
thrombin &
factor Xa
injection
SQ, IV
Effects begin
rapidly
Inhibits
synthesis of
clotting factors
oral
Begin slowly
Comparison between
Heparin & Warfarin
Duration
Monitoring
Antidote
Heparin
Warfarin
Effects fade
quickly
Effects persist
for days
aPTT
PT
Protamine
Sulfate
Vitamin K
Direct Thrombin Inhibitors
• Dabigatran etexilate (Pradaxa)
• Oral prodrug that undergoes conversion to dabigatran
• Advantages:
• Doesn’t require monitoring of anticoagulation
• little risk of adverse interactions
• same dose can be used for all patients regardless of age or weight
• Therapeutic uses
• Atrial fibrillation
• Knee or hip replacement
• Adverse effects
• Bleeding
• No specific antidote to reverse dabigatran-related bleeding
• Gastrointestinal (GI) disturbances
• Clinical considerations
•
Plasma levels peak about 1 – 3 hours after oral dosing. Not metabolized
by liver, excreted by kidneys. Half-life 13 hours. Take dose at same time
every day. No antidote
Direct Factor Xa Inhibitors
• Rivaroxaban [Xarelto]
– Binds directly with factor Xa to cause inactivation
– Prevention of DVT and PE after total hip or knee
replacement surgery
– Prevention of stroke in patients with atrial fibrillation
– Treatment of DVT and PE unrelated to orthopedic
surgery
– Oral
– No lab test
– No antidote
– Dosing at same time every day is required
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Antiplatelet Drugs
• Aspirin (ASA)
– Inhibition of cyclooxygenase
– Adverse effect
• Increases risk for GI bleeding
• Ticlopidine [Ticlid]
– Inhibits ADP-mediated aggregation
– Adverse effects
• Hematologic effects
• Clopidogrel [Plavix]
– ADP receptor antagonist
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Figure 52-1A Mechanism of platelet aggregation and actions of antiplatelet drugs.
ASPIRIN
Antiplatelet Drugs: ASPIRIN
• Aspirin (ASA)
– Irreversible Inhibition of cyclooxygenase
• Effects last ___ days?
• Indications for use
– Transient ischemic attack (TIA)
– Primary prevention of Ischemic Stroke
• Secondary prevention of Ischemic stroke
‒ Primary prevention of MI
‒ Secondary prevention of MI
– Acute MI
– Chronic stable angina
– Unstable angina
– Coronary stenting
•Adverse effect
– Bleeding; GI bleeding; Hemorrhagic stroke
– Enteric-coated tablets may not reduce the risk of GI
bleeding
CLOPIDOGREL
Antiplatelet Drugs: Clopidogrel
• Clopidogrel [Plavix]
– ADP receptor antagonist; Blocks P2Y12 ADP receptors on
the platelet surface, preventing ADP-stimulated aggregation
• Adverse effects: similar to aspirin
• Bleeding
• TTP (thrombotic thrombocytopenia purpura)
• Drug Interactions: PPI’s, CYP2C19 inhibitors
• Therapeutic uses
– Prevents blockage of coronary artery stents
– Reduces thrombotic events in patients with acute coronary
syndromes
• Prevents stenosis of coronary stents; also for secondary
prevention of MI, ischemic stroke, and other vascular
events
• Use with caution in combination with other drugs that promote
bleeding
Antiplatelet Drugs: glycoprotein IIb/IIIa
receptor antagonists
• Glycoprotein (GP) IIb/IIIa receptor antagonists
– Most effective antiplatelet drugs
– “Super aspirins”
– Reversible blockade of platelet GP IIb/IIIa
receptors
– Therapeutic use
• Acute coronary syndromes
• Percutaneous coronary interventions
Thrombolytic Drugs
• Alteplase [tPA]
– Binds plasminogen
Breaks down fibrin strands in the blood clot
• Uses
– Ischemic stroke- emergency management; must be administered within
2 hours of the onset of symptoms, preferably ASAP
• Risk of bleeding increases as time passes after clot occurred
– Massive pulmonary emboli
– Acute coronary thrombosis (acute MI)
– Deep venous thrombosis (DVT)
– Clearing clogged central catheters
• Adverse effects
– Bleeding: Risk for intracranial bleeding higher than with streptokinase
– If bleeding begins, treat with whole blood or blood products (packed red
blood cells, fresh-frozen plasma)
– Aminocaproic acid [Amicar] is last resort
–Fever
• Advantages
– Does not cause allergic reactions
– Does not induce hypotension
Question
During administration of alteplase [Activase], the
patient’s IV site starts to ooze blood around the
catheter. Which action by the nurse is most
appropriate?
A. Discontinue the infusion of alteplase.
B. Assess the patient’s vital signs.
C. Apply direct pressure over the puncture site.
D. Administer aminocaproic acid [Amicar].
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