Anticoagulation Flashcards by Matti Daniel

drugs used in coagulation disorders

Antiplatelets
anticoagulants
thrombolytics
coagulants

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role platelets play in homeostasis

They arrest bleeding from a damaged BV

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What happens when a BV is injured?

Exposure of the materials inside the BV will act as a catalyst to kick off a number of processes that lead to plugging the hole. BV constricts and platelet aggregation occurs.

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platelets are derived from

megakaryocytes, they have no nucleus

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What are the 3 steps to thrombus formation?

Adhesion and shape change
secretion
aggregation

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The adhesion step of thrombus formation is driven

The presence of collagen behind the endothelial layer of the BV

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WHat happens when there is damage to the endothelium

Platelets and clotting factors will find things that they normally do not see (collagen), kicking off coagulation.

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Exposure of platelets to what will allow platelets to adhere to collagen

VWF (vonwillebrand factor)

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What does GP1a bind? What does GP1b bind?

GP1a binds collagen
GP1b binds VWF

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How do endothelial cells inhibit platelet aggregation?

Prostacyclin (PGI2) is secreted to inhibit platelet aggregation
PGI2 also causes vasodilation

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What happens when we have damage to the endothelial layer

We lose the ability to locally inhibit platelet aggregation and lose the ability to locally cause vasodilation

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What is the 2nd step of platelet aggregation called?

secretion

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Platelets adhere to damaged portion of BV through

GP1a and GP1B

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What things are secreted after the adhesion of platelets

Platelets undergo degranulation and secrete ADP, thromboxane A2 (TXA2) and serotonin, which are pre-stored in platelet

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WHat do the secreted factors from platelet do?

These factors bind to receptors on other platelets and recruit these platelets to site of damageWhich factors are potent vasoconstrictors

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Thromboxane A2 and Serotonin

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degranulation leads to secretion of

ADP, txA2 and serotonin.
These bind to other platelets

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What receptor is an important pcol target to prevent platelet aggregation

ADP receptors

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TXA2 stimulates

recruitment of platelets to site of damage

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what is the final step in platelet aggregation

Platelatelet aggregation

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What happens to platelets in platelet aggregation phase

Platelets undergo a shape change that activates their GP IIb/IIIa receptor.

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What factors activate GP IIB/IIIa receptors

They are activated by the stimulation of ADP, TXA2 and serotonin, They can crosslink platelets to each other.

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What is fibrinogen? what does it do?

Fibrinogen crosslinks platelets via fibrinogen binding to its BIVALENT receptors

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What happens after platelets are cross linked by fibrinogen?

They fuse together and compact around site of damage. This becomes the substrate for formation of fibrin clot.

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WHat are some targets to inhibit platelet aggregation?

Inhibit GP IIb/IIIa receptors, TXA2, ADP receptors or inhibit thrombin

WHat are some drugs that have actions related to platelets

COX-1 inhibitors, ADP receptor inhibitors, PDE 3 inhibitors, protease activated receptor inhibitors

What does aspirin (ASA) inhibit

COX-1 (covalently)

How does aspirin interfere with platelet aggregation? what effects will that have on the body? WHat is its use?

inhibits TXA2 production. Prolongs bleeding time. Prevents arterial thrombin formation

Dose of aspirin that is used to inhibit platelet selectivity? Why this specific dose?

50-320 (81mg). At this dose, it leaves the prostacyclin production in endothelium alone and selectively inhibits thromboxane A2 production

What is produced by COX2

PHI 2 (prostacyclin)

indication of aspirin

prophylaxis and tx of arterial thromboxane disorders prevents thrombosis in unstable angina Can be used with thrombolytic therapy Prevents recurrence of strokes

Side effects of aspirin

prolongs bleeding GI bleeding due to cox-1 ihibition (increased risk of this in in NSAID pts)

WHat does COX 2 pruduce and what is its use?

Produces prostaglandin in endothelial cells. Vasodilation and inhibiton of platelet aggregation

What does COX 1 produce? What is its use?

Produces thromboxane A2 in platelets. Used for vasoconstriction and platelet aggregation.

What do selective COX 2 inhibitors do? what effect does this have?

They block synthesis of prostacyclin in endothelial cells, while not blocking TXA2. This leads to pro-platelet aggregation, increasing CV events.

What is the name of the two adp receptors involved in activating platelets

P2Y1 P2Y12

what receptors are P2Y1 and P2Y12 coupled to

P2Y1- GQ P2Y12- Gs

How does P2Y12 work?

it inhibits adenylyl cyclase

What are drugs that target this receptor

Prasgurel, clopidogrel, ticagrelor, cangrelor

WHat is the difference between the drugs that target P2Y12?

Prasgurel and clopidogrel undergo metabolism to active form (prodrugs) and are irreversible, while ticagrelor and cangrelor do not require activation and are reversible

What happens when we block P2Y12

Prevents platelet aggregation

Clopidogrel binds to? MOA?

binds to p2Y12. It is a prodrug that irreversibly blocks ADP receptors, inhibiting platelet activation.

Clopidogrel duration of action? indication?

Long duration of action. prevention of heart attack, stroke, peripheral vascular disease

What kind of drugs are clopidogrel and prasgurel?

Theinopyridine drugs (they are also prodrugs)

How is prasgurel activated?

Activated by esterase-1 CYP 3A4/2B6

prasgurel warnings

Old people can not use it due to risk of bleeding

Which P2Y12 drugs are reversible

Ticagrelor and cangrelor, they also have a short t1/2

Ticagrelor is a substrate for____ Onset and duration?

CYP3A4. Fast onset and short half life

What is cangrelor used for

Used to prevent thrombosis during PCI It is reversible, fast onset, short t1/s

Clopidogrel is activated by

CYP2C19

prasgurel needs _____ to cleave its bonds

esterase

What happens to prasgurel in the active form

The drug binds P2Y12 receptor and forms a disulfide cross link, becoming irreversible

What does dipyridamole do?

Inhibits PDE III in platelets and acts as aggregation inhibitor

dipyridamole can be used in conjuction with______ and ______ to prevent thrombosis

Warfarin and aspirin

What does citazole do?

Also a PDE III inhibitor. Used in a condition called intermittent claudification.

What does fibrinogen bind to? What does it do once bound?

Binds to GP IIb/III a to crosslink adjacent platelets

What do GPIIb/IIIa inhibitors do?

They inhibit the ability of fibrinogen to crosslink the platelets

Name GP IIb/IIIa inhibitor drugs

Abiciximab Eptifibatide tirofiban

All of the GPIIb/IIa drugs ROA, they are all used in conjuction with

All IV In conjuction with PCI

What type of molecule is eptifibatide

Cyclic peptide

What does Eptifibatide do?

Inhibits fibrinogen binding to decrease platelet aggregation

Eptifibatide MOA

arginine (R), glycine (G), aspartic acid (D) motif is the basis of binding, which exists in fibrinogen to bind GPIIB/IIIA. So it is a perfect mimic

What kind of molecule is tirofiban

small molecule

MOA of tirofiban

R,G,D motif that acts as a mimic to bind to gPIIb/IIIa

tirofiban can be compined with____

heparin to treat acute coronary syndrome

What kind of drug is abriximab

Antibody

What is an important thing about abciximab that we should know

long duration of action, increased risk of bleeding

Abciximab MOA

Binds to GPIIb/IIIa and inhibits platelet aggregation

What are eptifibatide, tirofiban,abciximab indicated for?

all given IV for unstable angina and stents to prevent thrombosis

What does thrombin do?

activates platelets

how does thrombin activate platelets

Via protease activated receptor (PAR)

MOA of thrombin on platelets

proteolytic cleavage of PAR-1 on platelet surface

PAR is activated by

thrombin

why is cox 1 targeted in antiplatelet drugs

cox 1 synthesizes txa2,

why is GPiib/iiia a target for antiplatelet activity

fibrinogen (protein that is cleaved to generate a fibrin clot) is bivalent and binds to two GPIIb/IIIa receptors to crosslink platelets. we can inhibit cross linking of platelets by targeting GPIIb/IIIa

why is P2Y12 a target for antiplatelet activity

It secretes ADP, stopping this can inhibit aggregation

what does thrombin do?

cleaves fibrinogen to fibrin. activates PAR

How does thrombin activate platelets

cleavage of PAR-1 receptors on platelet surface

Vorapaxar MOA

inhibits I/A of thrombin with PAR, inhibits thrombin activation of platelet aggregation

is vorapaxar reversible?

yes

Know structures of the drugs