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Angeli - N929 Pharmacology > Exam 3: Anticoagulants, Antiplatelet agents, and Thrombolytics > Flashcards

Exam 3: Anticoagulants, Antiplatelet agents, and Thrombolytics Flashcards

1
Q

Define:

Anticoagulants

Antiplatelet agents

Thrombolytics

Herbal Agents

A
  • Anticoagulants - prevent clot formation or extension of existing clot
  • Antiplatelet agents - ↓ plt aggregation

** 1st 2 do not break down clots **

  • Thrombolytics - converts endogenous plasminogen to the fibrinolytic enzyme PLASMIN to dissolve newly formed blood clots
  • Herbal Agents - 3Gs! various mechanisms
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2
Q

intrinsic anticoag mechanisms:

4 major counter-regulatory pathways

A
  • fibrinolysis
  • TFPI - tissue factor plasminogen inhibitor
  • protein C system
  • serine protease inhibitors (SERPINs)
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3
Q

prevention of coagulation

A
  • Random blood clotting is normally prevented by the presence of endogenous anticoagulation factors
    • The capillary endothelium is the main source of anticoagulation factors
  • Prevention of blood coagulation outside of the body
    • Siliconized containers (stored donated blood)
    • Heparin in CPB or artificial kidney machines
    • Citrate Ion
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4
Q

TFPI - Tissue Factor Plasminogen Inhibitor

A
  • is a polypeptide produced by endothelial cells
  • acts as a natural inhibitor of hte extrinsic pathway by inhibiting TF-VIIa complex
  • “TFPI - TF? Put It (VIIa) away!”*
  • Stops the extrinsic pathway from starting.*
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5
Q

Protein C pathway (APC)

A
  • protein C and S are buddies, they go around together like how vWF and F8 go together.
  • (don’t have to memorize all of this)
  • just know that protein C is a natural anticoagulant in our bodies
  • Coagulation propagation is inhibited by the Protein C pathway that primarily consist of four key elements
    • Protein C is an enzyme with potent (natural) anticoagulant, profibrinolytic and anti-inflammatory properties. It is activated by thrombin to form activated protein C (APC) and acts by inhibiting activated factors V and VIII (with Protein S and phospholipids acting as cofactors)
    • Thrombomodulin - A transmembrane receptor on endothelial cells (that binds to thrombin), prevents the formation of the clot in the undamaged endothelium
    • Endothelial protein C receptor is another transmembrane receptor that helps in the activation of Protein C
    • Protein S is a vitamin K-dependent glycoprotein, synthesized by endothelial cells and hepatocytes. activity is by virtue of free form while the bound form acts as an inhibitor of the complement system and is up regulated in the inflammatory states, which reduce the Protein S levels thus resulting in procoagulant state. It functions as a cofactor to APC in the inactivation of FVa and FVIIIa.
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6
Q

SERPIN: antithrombin

know what factors this mainly works on

A
  • serpin = serum protease inhibitor (google)
  • Previously known as AT III - is the main inhibitor of thrombin.
  • Binds and inactivates thrombin, factor IIa, IXa, Xa, XIa, and XIIa.
    • (thrombin, 2a, 9a, 10a, 11a, 12a)
  • The enzymatic activity of AT is enhanced in the presence of heparin. (lovenox/heparin)
  • AT is synthesized in the liver and its plasma half-life is 2.5-3.8 days
  • Deficiency:
    • Hereditary AT deficiency is estimated to be 1 in 2,000-5,000
    • Acquired deficiency i.e. prolonged heparin infusions >4-5 days decreased plasma AT activity by 50-60% of normal - downregulation

“Antithrombin 2 and 10, what’s gon’ help it? HEP-A-REN”

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7
Q

prevention of blood coagulation (for blood) outside of the body:

citrate ion

A
  • Citrate Ion
    • Any substance that deionizes the blood calcium will prevent coagulation
    • Negatively charged citrate ion combines with positively charged calcium in the blood to cause an un-ionized calcium compound
    • After injection, the citrate ion is removed by liver and is polymerized into glucose or metabolized
  • If there is liver damage or massive transfusion, the citrate ion may not be removed quickly enough, and this can greatly depress the level of calcium ion in the blood
  • if citrate > Ca++ in pRBCs, will bind to Ca++ in plasma. IF you give a lot of it then the citrate will build up bc the liver can’t clear it fast enough.
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8
Q

Anticoagulants: name 5 kinds/brands

A
  • vitamin K antagonists
  • unfractionated heparin
  • LMW heparin and fondaparinux - lovenox
  • direct thrombin (IIa) inhbitors - pradaxa
  • direct PO anticoagulants
    • IIa inhibitors - pradaxa
    • Xa inhibitors - xarelto, eliquis (= rivaroxaban, apixaban…)
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9
Q

Coumadins:

class

origins

A
  • vitamin K antagonists - remember 2, 7, 9, & 10!
  • coumarin was 1st synthesized in 1868. It’s used in the pharmaceutical industry as a precursor reagent in the synth of a number of synthetic anticoagulants, the most notable being warfarin (Coumadin)
  • some potent rodenticides work by the same anticoag mechanism of vitamin K antagonism
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10
Q

Coumadin MOA

A
  • Warfarin (Coumadin®) inhibits vitamin K which results in the hemostaYcally defecYve vitamin-K dependent coagulation proteins (II, VII, IX, and X)
  • This effect is caused by competing with vitamin K for reactive sites in the enzymatic processes for formation of prothrombin and the other clottng factors, thereby blocking the action of vitamin K
  • Platelet activity is not altered - on the coagulation cascade side of things. giving a pt plts is not going to affect what’s going on here!
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11
Q

Coumadin PK

A
  • Rapidly and completely absorbed
  • 97% protein bound
  • Long elimination half-time of 24-36 hours after oral administration
  • Not suitable to use in the parturient –crosses placenta and is severely teratogenic

-would give them Heparin

• Metabolized to inactive metabolites that are conjugated and excreted in bile and urine

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12
Q

coumadin

dosing

when are effects seen

testing to measure therapeutic-ness levels

considerations

A
  • effective in prevention of thromboembolisms
  • 2.5-10 mg orally, dose varies among pts (pic of the rainbow of colored pills that it can come in)
  • Onset 3-4 days
  • DOA of single dose is 2-4 days
    • onset = DOA
  • effects are seen on INR in 8-12 hrs, d/t depletion of Factor VII, however full clinical effects are not appreciated for several days
    • long T1/2 and variable effects bc factors have different half-lives
  • measured by PT/INR
  • considerations: if the pt eats a diet of green-leafy veg’s (high in Vitamin K) → must ↑ dose!
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13
Q

coumadin coagulation is dependent on the factor with the longest T1/2

A

65 hrs is factor II

[remember that coumadin works on 2, 7, 9, 10!]

then X is 40 hrs - IX is 25 hrs - VII is 5 hrs

(VII - this is why INR changes within 8-12 hrs, despite not having full clinical effects for a lot longer than this amt of time!)

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14
Q

INR goals and coumadin:

when would you want a goal INR or 2-3

A
  • afib
  • PE, VTE
  • prevention of VTE in high-risk surgery
  • tissue heart valves

“2-3 TAPP”

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15
Q

INR goals and coumadin:

when would you want a goal INR or 2.5-3.5

A
  • mechanical heart valve
  • prevention of recurrent MI
  • hx of VTE with INR 2-3
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16
Q

ex of coumadin mgmt before surgery

A
  • It is prudent to check the PT/INR
  • Minor surgery –discontinue 1-5 days preop for PT 20% within baseline
    • ​you might not want 100% of medication gone
    • Reinstitute the regimen 1-7 days post-op
  • Immediate surgery (24-48 hours) or active bleeding – Vitamin K
    • 2.5mg-20mg orally or 1-5mg IV at rate of 1mg/min
    • PT to normal range within 4-24 hours
    • still slow
  • Emergency –FFP or 4-factor concentrate (Kcentra) - remember you can’t give 3-factor concentrate for coumadin!
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17
Q

heparin: where does it come from?

A
  • Heparin is a naturally occurring polysaccharide that inhibits coagulation
    • Heparin is released endogenously by mast cells and basophils and used widely as an anticoagulation drug
  • Unfractionated heparin is derived from porcine intestine or bovine lung and is a mixture of sulfated glycosaminoglycans that produce an anticoagulant effect by binding to and enhancing the naturally occurring effects antithrombin
    • Unfractionated heparin is more unpredictable than LMWH
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18
Q

unfractionated vs LMW Heparin

longer chains inhibit what

shorter chains inhibit what

A
  • longer chains inhibit factor X
  • shorter chains inhibit factor II
  • LMWH has more shorter chains
  • needs the green sequence on the end to bind to antithrombin, in order for antithrombin to do its thing on factors II and X
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19
Q

unfractionated heparin

A
  • Binds to antithrombin (antithrombin III)
    • Enhances 1,000 times the ability of antithrombin to inactivate a number of coagulation enzymes (thrombin (IIa), factors Xa, XII, XI and IX) - 2, 9, 10 … 11, 12
    • heparin - II and X!
  • Functions as an anticoagulant by accelerating the normally occurring antithrombin-induced neutralizaYon of activated clotting factors
  • Neutralized thrombin prevents the conversion of fibrinogen to fibrin

2 and 10!!

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20
Q

unfractionated heparin preparations

A
  • LMW heparin
  • only 1/3 of administered heparin binds to antithrombin (that dark green setion in picture), and this fx is responsible for its anticoag effect
  • the USP (US pharmacoepia) deinfes 1 unit of activity as the amount of heparin that maintains the fluidity of 1 mL of citrated plasma for 1 hr after re-calcification (wtf does that mean)
  • heparin must contain at least 120 units/mL
  • but 1 vial might be 122 units, and then another one have 125 units
  • bc commercial preparations vary in the # of USP units per mL, it is prescribed in UNITS
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21
Q

unfractionated heparin PK

A
  • poor lipid solubilty (large molecule)
  • cannot cross lipid barriers in significant amts
    • does not cross placenta - safe in obstetrics
  • once injected, it circulates bound to plasma proteins
    • this occurs instantly
    • DOA: 1.5-4 hrs
    • injected heparin is destroyed by an enzyme in the blood - heparinase
  • ​most commonly monitored by biological activity - ACTs!
    • stands for activated clotting time
    • tells you the seconds it takes the blood to clot
  • dose-response relationship
    • 100 units/kg IV half-life is 56 minutes
    • 400 units/kg IV half-life is 152 minutes
  • ↓ in body temp PROLONGS T1/2 - that blood is moving slower bc it’s colder, so heparinase enzyme can’t get to it as quickly as it normally would
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22
Q

clinical monitoring and uses of unfractionated heparin

(3 tests you can run)

A

monitoring heparin:

  • aPTT (activ plasma thromboplastin time)
    • 1.5-2.5x pre-drug value (30-35 seconds)
  • ACT (activated clotting time)
    • normal baseline is 60-80
    • get a baseline, 3-5 minutes post administration, 30 min-1 hr intervals post-administration (decide on this interval with surgeon so you can keep an eye on when to re-dose)
    • make sure you communicate the value with surgeon
  • Heptem is like the viscoelastic testing, but it takes into account that the pt got heparin - just need to tell the lab that pt got heparin

Clinical uses of heparin:

  • subq VTE/PE prophylaxis - ERAS cases, ortho, post-MI, HD
  • warfarin “bridge”
  • vasc or non-CPB cases vary - ACT > 200-300 seconds
    • fem-pop bypass
    • aneurysm clipping
  • CBP - ACT > 400-480 seconds (inadequate to go on pump if <180)
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23
Q

unfractionated heparin dosing examples (4)

A
  • prophylaxis of VTE - ERAS post-epidural, for example for bowel cases/GYN
    • ​5000 units SC q8-12 hrs
  • tx ot VTE
    • 5000 units IV, followed by gtt
    • goal ptt 1.5-2.5x control value
  • CBP
    • 400 units/kg IV (remember goal ACT was > 400)
  • vascular interventions
    • 100-150 units/kg IV (remember goal ACT was >200-300)

^^​Use TBW!

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24
Q

Heparin SEs

A

hemorrhage/hematomas

HIT - thrombocytopenia - have to use argatroban if they have this

allergic rxn

hypotension with large doses

altered protein binding

chronic exposure can progress to ↓ in antithrombin activity

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25
Q

intraspinal hematoma

A
  • 0.1 per 100,000 pts per year
  • more likely to occur in anticoagulated or thrombocytopenic pts, pts with neoplastic dz, liver dz, or ETOH
  • IV heparin and neuraxial anesthesia
    • 1 hr delay between needle placement and administration of heparin
    • cath should be removed 1 hrs before heparin administration and 2-4 hrs after last heparin dose
    • monitor PTT or ACT
  • just need to know the guidelines for how long to hold heparin before placing/moving needle

me: does that mean that once the needle is in you can’t give any more heparin, or that you can but you just have to wait 1 hr? or is that saying that if you gave heparin BEFORE the needle, you have to wait 1 hr before placing the needle? lord help me.

26
Q

heparin formularies

A
  • 2006 - 2008 neonates received potentially fatal doses of heparin
  • 2006 - 6 premies in Indiana got 1000x heparin dose for a line flush, 3/6 died
  • 2007 - 3 pts in LA got vials that has 10,000 units/mL instead of 10 units/mL for hep-locked IVs
  • 2008 - 17 babies over-dosed on heparin, 1 died

now they have to say the total units in the vial, then the total mLs

common to have the WRONG vial stocked, or zofran stocked instead of heparin

27
Q

HIT - Heparin-Induced Thrombocytopenia

(2 categories)

A
  • heparin-dependent antibodies that aggregate plts and leads to consumption which produces thrombocytopenia
  • mild (Type I) - 30-40% of heparin-treated pts
    • non-immune mediated
    • plt <100,000 cells/mm3
    • typically presents 3-15 days after initiation of therapy
  • severe (Type II) - 0.5-6% of heparin-treated pts
    • immune-mediated
    • plts <50,000 cells/mm3
    • typically presents 6-10 days after initiation of therapy
  • The clinical suspicion of HIT is then confirmed with lab tests for antibodies
  • Mgmt of pts with a hx of HIT:
    • alternative anticoags (direct thrombin inhibitors), but not many options
    • following the disappearance of HIT antibodies, heparin may be used again
    • if it was mild/type I, and they didn’t have antibodies they could potentially get heparin the next time
28
Q

allergic rxns to heparin

A
  • obtained from animal tissues, so use in pts with preexisting hx of allergy (TO WHAT)
    • be cognizant of religious beliefs too!
  • fever, urticaria, hd changes
29
Q

antithrombin deficiency

(1st review what heparin does - MOA)

A
  • remember what heparin does: it binds to and enhances the effects of antithrombin. antithrombin prevents thrombin from converting fibrinogen to fibrin*
  • (way way back review):*
    1. TF changes X to Xa*
    1. Xa changes prothrombin to thrombin**
    1. thrombin changes fibrinogen to fibrin**

^ antithrombin works to block Xa from converting prothrombin, AND blocks action of thrombin itself

TF - 10 - prothrombin - fibrinogen (The fuck, ten, pro-thrombin, be fib-bin) IDK.

  • pts with antithrombin deficiency will have a resistance to heparin
  • no antithrombin = nothing for heparin to bind do
  • 22% of pts undergoing cardiac surgery have this
  • pts who received intermittent/continuous heparin may dev a progressive, paradoxical reduction of antithrombin
  • ↓ in antithrombin may paradoxically ↑ the thrombotic tendency
    • estrogen-containing contraceptives also ↓ antithrombin’s ability to inhibit Xa
  • when heparin resistnace is 2/2 antithrombin deficiency, give it back!
    • 2-4 units FFP in adults
    • or antithrombin concentrate
30
Q

heparin reversal

A

protamine for heparin neutralization

1-1.5 mg for each 100 units of heparin that was given

* this is more for the most recent administration, ~ last 2 hrs or so. You’re not going to reverse ALL the heparin you gave throughout the case, and also some of it has probably been metabolized if it’s been a long case

31
Q

LMWF

A
  • lovenox, Enoxaparin
  • low molec wt heparin are derived from standard commercial grade unfractionated heparin
    • chemically depolymerized
    • yields fragments 1/3 the size of unfractionated heparin
  • depolymerization results in changes to the anticoag profile, PK and effects on plt fn
32
Q

compare LMWH to unfractionated heparin:

anti-activated factor X to anti-activated factor II ratio

molecular wt

protein-binding?

T1/2

A
  • anti-activated factor X to anti-activated factor II
    • LMWH 4:1 to 2:1
    • unfx 1:1
    • smaller, so LMWH affects factor X more, factor II less
  • molecular wt
    • LMWH 4,000-5,0000 daltons
    • unfx 30,000 daltons
  • protein binding
    • LMWH = less
    • unfx = STRONGLY
  • T1/2
    • LMWH: 24 hrs, qd dosing
    • unfx: T1/2 2-3 hrs, repeat dosing q8-12 hrs
33
Q

LMWH: MOA and dosing

A
  • enoxaparin, Lovenox binds to and accelerates antithrombin
    • inhibits factor Xa and IIa (Xa > IIa)
    • factor Xa converts prothrombin to thrombin, so lovenox’s inhibition of this process results in ↓ thrombin, and prevention of fibrin clot formation
    • remember TF (FIII), X, pro-thrombin (FII), be fib-bin (FI)
    • factor III → (X) → factor II → factor I
    • DVT prophylaxis dose example: 30 mg SQ every 12 hrs
34
Q

LMWH: adv’s and disadv’s

A
  • advantages
    • ↓ dosing frequency and no need for monitoring
    • more predictable PK
    • ↓ effects on plt fn
    • ↓ risk for HIT
  • disadvantages
    • more expensive
    • surgery must be delayed for 12 hrs after last dose
    • protamine only neutralizes ~ 65% of anti-factor X activity of LMWH - a more complete reversal takes FFP (basically the protamine is better at reversing unfx heparin)
35
Q

DOACs - direct oral anticoagulants:

classes/brands

uses

adv’s

A
  • brands
    • Direct thrombin (IIa) inhibitor = dabigatran (Pradaxa)
    • Direct Factor Xa inhibitor - rivaroxiban, apixaban, edoxaban
  • uses - as an alternative to warfarin
    • tx of VTE
    • prevention of embolic stroke
    • prophylaxis in pts undergoing surgery
  • advantages
    • rapid onset with peak effect in 2-4 hrs
    • predictable PD
    • minimal drug interactions
    • no routine labs
36
Q

Direct Thrombin (IIa) inhibitor:

brand

metab

T1/2

reversal

A

Factor Xa inhibitors ahve xa in them, so you know IIa (thrombin) inhibitor is the one that’s left: pradaxa/Dabigatran!

  • Dabigatran, Pradaxa
    • ​metabolized by renal elim ~80% (one of these things is not like the other)
    • T1/2 is 12 hrs, unless renally impaired
    • ↓ creat clearance - ↓ dosing in general, and preop hold it longer
  • monitoring
    • some sort of coag assay
      • dilute thrombin time - more reliable/precise measurement
      • aPTT - but a normal aPTT doesn’t exclude residual anticoag effects - eh maybe
      • ROTEM might correlate, but less specific than thrombin time
  • Reversal
    • idarucizumab (PRAXBIND) - specific antidote for pradaxa
    • binds to dabigatran with 350x higher affinity than thrombin
    • T1/2 is 45 minutes
37
Q

Direct Factor Xa inhibitors (3 of them)

A
  • xa in the names!
  • rivaroxiban (Xarelto)
  • apixaban (Eliquis)
  • edoxaban (Savaysa)
  • metabolism: hepatic - 65-70%
  • monitoring
    • coag assay - anti-Xa (not common)
    • ROTEM - NOT sensitivie
    • PT, but only rivaroxiban
38
Q

flowchart of mgmt of bleeding for pts on DOACs

A
  1. assess & stop anticoag
  2. non-pharmacologic care - IV fluids, compress site of bldg
  3. modify PK of agent - activated charcoal in ED, HD for dabigatran
    • w/i 2 hrs for dabigatran, edoxaban
    • 6 hrs apixaban (6-apix)
    • 8 hrs rivaroxaban
  4. blood tx - pRBCs, FFP (not great tho), plt if thrombocytopenic or on antiplts also
  5. replenish coag factors
    • aPCC or 4-factor PCC preferred
    • rfVIIa NOT recommended
39
Q

General mgmt of DOAC-treated pts undergoing surgery

A
  • 1-2 days is probably safe
  • min bldg risk procedures are likely safe to undergo with no DOAC interruptions
    • dental procedures
    • cataracts
    • skin bx’s
  • low bldg risk procedures - stop 24 hrs before elective surgery
    • hernia repair
  • high bldg risk procedures - stop 48 hrs before elective surgery
    • cardiac, intracranial surgeries
    • longer interruption for dabigatran and renally impaired pts
    • additional studies are ongoing to assess standardized periop mgmt protocols in DOAC-tx’d pts
40
Q

reversal agents for NOACs (= DOACs)

3 brands

A
  • Pradaxa (dabigatran) = Praxbind (idarucizumab)
    • $3500
    • directly binds pradaxa
  • Andexanet alpha = Xa = apixaban, rivaroxaban, edoxaban + heparins
    • competes with Xa for binding them (more Xa means more prothrombin converted to thrombin, more clotting)
    • $58,000
  • Prothrombin complex concentrates = for vitamin K antagonists (Warfarin)
    • contains factors II, IX, X … VII, protein C and S
    • $2-5000
41
Q

antiplt agents

(name the 3 classes)

A

COX inhibitors (cyclooxygenase inhib’s)

P2Y12 receptor antagonists

glycoprotein IIb/IIIa inhibitors

42
Q

antiplts (what do they do, what are the different mechanisms by which this can be accomplished)

A
  • they suppress plt fn
  • antiplt therapy is indicated for pts at risk for CVAs, MI, or other vasc thrombosis complications
  • mechanisms for plt suppression
    • COX/TXA2 inhibition
    • ADP receptor antag
    • GP IIb/IIIa antag
43
Q

ASA

MOA

dose

how long would you hold this preop

A
  • antithrombotic bc it inhibits plt aggreg
  • specifically, inhibits thromboxane A2 synthesis by interfering with the COX1 and 2 enzymes, thereby interfering with the release of ADP by plts → no plt aggregation
  • effects are irreversible and last the life of the plt (8-12d)
  • dose: 81-325 mg
44
Q

ASA and COX

A
  • COX is rendered non-functional bc the acetyl group of ASA causes acetylation of COX
  • COX is the rate-limiting enzyme in the coversion of arachidonic acid to thromboxane A2
  • remember that arachidonic acid → prostaglandin → thromboxane A2 (causes plt aggregation!)
45
Q

NSAIDs

(3 brands)

MOA

A
  • ketorolac, naprosyn, ibuprofen
  • same mechanism of action as ASA (nonselective COX inhibitors)
  • more temporary (24-48 hrs), so just hold them 1-2 days before surgery
46
Q

mgmt of ASA in the perioperative period:

primary vs secondary prophylaxis

A
  • primary prophylaxis (HLD without CVD) - ASA should be continued up to and including the DOS
    • ASA may be held for a few days at the discretion of the surgeon d/t possibility of ↑ r/f bldg
  • secondary prophylaxis (afib, MI, PCI) - ASA should be continued up to and including DOS
    • ASA stoppage needs explicit discussion with cards/vascular physician for risk-benefits
  • specific circumstances where you HOLD ASA:
    • intracranial
    • middle ear
    • posterior eye
    • intramedullary spine surg
    • possibly in prostate surgery
    • this decision must be documented
47
Q

P2Y12 receptor antagonists

A
  • Plavix and Brilinta (Ticagrelor)!
  • inhibit plt activation and aggregation
  • irreversible binding of active metabolite to the P2Y12 class of ADP receptors that are on plts
  • Plavix is a prodrug, must be metabolized by CYP450 enzymes. There exists a genetic mutation in that 15% of ppl can’t metabolize the drug (so it’s not doing shitttttt)
  • Brilinta does not need hepatic activation! also has better mortality rates in pts with ACS
  • must be d/c’d 7 days prior to elective surgery
  • plt fn studies are unreliable for plavix, but inhibition of P2Y12 ADP receptor is available
  • plt tx is useful for emergent surgery and restoring hemostasis
48
Q

Indications for P2Y12 receptor antagonists

A
  • 2o prevention of MI, CVA
  • PCI
  • ACS
  • PAD
  • PCI causes endothelial and medial damage that heals by neointimal formation, usually within 2-6 wks with BMS (after that there’s not much more risk of a thrombotic event bc of the endothelial layer)
  • DES, re-endothelialization and neointimal healing are delayed, keeping stent struts exposed, which can cause plt aggregation and thrombus formation
  • elective procedures should be delayed at least 6 wks, but ideally 6 months after DES placement
49
Q

antiplts and anesthesia

A
  • 2o prevention with ASA ↓s mortality up to 30% in HR groups
  • withdrawal of ASA in pts with CAD is associated with 2-4 fold increase in death/MI
  • ASA and P2Y12 receptor antagonists act synergistically (why we do DAPT)
  • >10% of ACS in the perioperative pd are precipitated by preop cessation of ASA
  • pts with PCIs are at high risk of thrombotic events, esp in the 1st 3 months after insertion
50
Q

plt glycoprotein IIb/IIIa antagonists

A
  • act at the corresponding fibrinogen receptor that’s important for plt aggregation
  • blocks fibrinogen which is the final common pathway of plt aggregation
  • used in ACS, angioplasty failures, PCI thrombosis
  • abciximab (ReoPro), tirofiban (Aggrastat), and eptifibatide (Integrilin)
  • giving these directly at the site now, instead of infusions that go everywhere
51
Q

plt glycoprotein IIb/IIIa antagonist monitoring (difficult)

A
  • their effects can be monitored with ACTs and reversible with the clearance of the drug
  • ACT maintained between 200-400 seconds
  • most of the agents are renally excreted and have T1/2’s around 2.5 hrs - except abciximab which has a T1/2 of 12 hrs, and clinical effects of 24 hrs
  • plt counts should be monitored, and therapy d/c’d if thrombocytopenia develops (<100,000 cells/mm3)
  • the effects of these drugs can be reversed with plt infusions (to be (IIb) a plt!)
  • these are the pts that Dr. Funk remembered were bldg from ears, nose, orifices
52
Q

herbal anticoagulants (6)

BOARDS question

A
  • garlic: inhibits plt aggregation, stop 7d prior
  • gingko: inhibits plt aggreg factor, stop 36 hrs prior
  • ginseng: inhibits plt aggregation and lowers BG. Check PT/PTT/glucose, hold for 24hr-7days
  • black cohosh: “useful for menopausal sx’s”. contains small amt of anti-inflamm compounds, such as salicylic acid
  • fish oil: prevent/tx atherosclerotic CVD (800-1500 mg/day). Also used to lower TGs (>4g/day). Dose dependent bldg risk increases with dose >3g/day
  • feverfew: “prevents migraines”. ↑s risk of bldg bc it itself inhibits plt aggregation, and also enhances other antiplt drugs and warfarin
53
Q

fibrinolysis:

talk about initial clot

and what breaks it down

A
  • when a clot is initially formed, it’s a semi-solid mass of plts, and a fibrin mesh that traps WBCs and plasma
  • the clot solidifies as plts contract and squeeze out H2O
  • plasminogen is a serum protein that is absorbed into that clot as it’s forming
  • plasminogen is cleaved into plasmin, which breaks down fibrin and fibrinogen
    • tissue plasminogen factor and urokinase-type plasminogen activators are released from the capillary endothelium
54
Q

thrombolytics:

fibrin-specific agents

non-fibrin-specific agents

A
  • fibrin-specific
    • alteplase
    • reteplase
    • tenecteplase
  • non-fibrin-specific
    • streptokinase
55
Q

thrombolytics: what do they do

A
  • possess inherent fibrinolytic effects or enhance the body’s fibrinolytic system by converting plasminogen to plasmin (which is a fibrinolytic enzyme)
  • more capable of dissolving newly formed clots (plt rich and weaker fibrinogen bonds)
  • ~6 hrs, miiiight use at 7 hrs - this is also extending bc they’re going and injecting the drug right at the site of the clot instead of systemic infusions
56
Q

thrombolytics (kind of repetitive)

uses

contraindications

brands

A
  • converts plasminogen to the active form, plasmin
  • plasmin breaks down fibrin (into fibrin degradation split products)
  • used to restore circulation thru a prev occluded vessel
    • STEMI
    • acute ischemic stroke
    • acute massive PE
  • contraindicated in trauma, severe HTN, active bldg, pregnancy
  • urokinase, streptokinase, alteplase (tPA)
  • hemorrhage/bldg risk is the most common risk
  • often 6-hr window
57
Q

alteplase

(recombinant Tissue Plasminogen Activator)

A
  • fibrin-specific thrombolytic, synthesized by endothelial cells
  • limited to use in 1st 3-6 hrs of ischemic stroke
  • can be systemically or directly into embolism (make sure all indwelling lines are in BEFORE giving this)
  • short T1/2 - 5 minutes
  • usually given as bolus, then gtt
58
Q

streptokinase

A
  • plts can have a rxn to it
  • is not an enzyme, but it noncovalently binds to plasminogen and converts it to plasminogen-activator complec that acts on other plasminogen molecules to gen plasmin
  • T1/2: 20 minutes
  • as a bacterial product (comes from streptococci), may stimulate antibody production, and cause subsequent allergic rxns
  • is the least expensive of all the thrombolytic drugs - used more internationally
59
Q

thrombolytic AEs

A
  • bldg, duh.
  • re-thrombosis (you just broke down that clot but you need to give something that will prevent further clotting still)
    • anticoags such as heparin are usually co-administered and continued after thrombolytic therapy is done
  • efficacy depends on the age of the clot. older clots have more cross-linkage and are more compacted = more difficult to dissolve
  • surgery and puncture of a non-compressible vessel (like vessels where we put CVADs) is contraindicated within a 10-day pd after the use of thrombolytics
60
Q

summary of anticoags, antithrombotics, thrombolytics

A
  • anticoags delay or prevent clotting and have no effect after the clot is formed (that would be thrombolytics)
  • antithrombotic drugs influence the formation of a clot by inhibiting plt activity
  • thrombolytics possess inherent fibrinolytic effects that can acutally break down a clot

Angeli - N929 Pharmacology (12 decks)

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