Pharm E2- Heme

order of events in hemostasis

1. Vasospasm: local mediators (TXA2)

2. Plt plug formation: collagen, mediators, plt adherence/aggregation

3. Fibrin clot formation: prothrombin → thrombin → fibrinogen → fibrin

4. Fibrinolysis: plasminogen → plasmin → fibrin → split products

Where is thrombomodulin and what does it do in hemostasis?

on surface of cells

help antagonize clotting factors by binding to thrombin, complex activates protein C and inactivates factors V and VIII

Where is antithrombin III and what does it do?

circulating

binds thrombin and inactivates

What works w/ antithrombin III?

heparin

Where is Heparin and what does it do?

mast cells

binds antithrombin III, activates 100-1000 fold to inactivate factors XII, XI, X, and IX

What does prostacyclin (PGI2) do?

inhibits platelet activation

What does thromboxane A2 (TXA2) do?

stimulate platelet activation

What does plasmin do?

digests fibrin, inactivates factors V, VIII, and XII (dissolves clot)

Explain platelet activatin

collagen exposed → GP1b bind vWF → collagen binds GPIa/IIa → releases TXA2 and ADP → ADP and TXA2 cause conformational change exposing GPIIb/IIIa (big targets for plt meds)

fibrinogen binds GPIIb/IIIa cross linking alt plug → thrombin interactsw/ PAR1 and PAR4 receptors to stimulate plt activation

ADP activates P2Y1/PDY12 receptors which activate plts

How does aspirin affect platelet activation?

irreversible acetylates COX enzymes (nonselective for 1 and 2)

• inhibits TXA2 for life of plt- 7-10 days (COX-1)

• inhibit PGI2 partially in epthelium (COX-2)

At what dose of ASA is COX maximally inhibited?

160 mg/day (higher doses inhibit PGI2 → limits activity)

Where is COX 2 expressed?

endothelial cells and w/ inflammation

What are possible SE of NSAIDs?

GI- dyspepsia, GERD, PUD, bleeding, bruising

How long does ibuprofen, diflunisal inhibit COX for?

24 hrs

How long does naproxen, diclofenac, and indomethacin inhibit COX for?

48 hrs

How long does piroxicam inhibit COX for?

72 hrs

What do ADP receptor blockers do?

inhibit ADP binding to P2Y1 + P2Y12 receptors

direct inhibition of fibrinogen binding to GPIIb/IIIa

interferes w/ binding of vWF

What does P2Y1 receptor do?

pathway induces shape change and aggregation

What does P2Y12 receptor do?

inhibits cAMP induced inhibition of plt activation

What are the 3 main ADP receptor blocker drugs?

clopidogrel (Plavix)

ticagrelor (brilinta)

Prasugrel (effient)

What are ADP receptor blockers synergistic w/?

ASA

What are indications for ADP receptor blockers?

prevent stroke, MI, peripheral artery dz, angioplasty

How does clopidogrel (plavix) prodrug work?

binds sulfur on P2Y12 receptor; synergistic w/ ASA

What are adverse effects of clopidogrel (plavix)?

hemorrhage, neutropenia, TTP, N,V,D, rash

How does Prasugrel (effient) prodrugwork?

binds P2Y12 receptor; synergistic w/ ASA

(recommended over clopidogrel due to more plt inhibition)

What are adverse effects of Prasugrel (effient)?

HTN, HA, hyperlipidemia, bleeding risk

How does Ticagrelor (Brilinta) work?

binds P2Y12 receptor (NOT a prodrug, but has active metabolite → extends duration of action)

synergistic w/ ASA

(recommended over clopidogrel due to more plt inhibition)

What are adverse effects of Ticagrelor (Brilinta)?

increased uric acid (risk for gout), major bleeding, dyspnea

What are 3 glycoprotein IIb/IIIa blockers?

Abciximab (ReoPro) IV

Eptifibatide (Integrilin) IV

Tirofiban (Aggrastat) IV

What do monoclonal antibody drugs end in?

mab

What is Abciximab (ReoPro) IV?

humanized monoclonal antibody- target IIb/IIIa receptors and prevent fibrinogen from forming link b/t platelets

immediate onset, stays bound 18-24 hrs after infusion stopped,

expensive

angioplasty w/ ASA and heparin, prevents restenosis

what are adverse effects w/ Abciximab (ReoPro) IV?

bleeding, thrombocytopenia, immunogenic develop antibodies (less effective)

What can you use as an alternative to Abciximab (ReoPro) if you have an issue w/ immunogenicity?

Eptifibatide (Integrilin) - smaller target for immune system to see, less likely to react

Tirofiban (Aggrastat) - not peptide/protein related so lowest risk for immunogenicity

Which glycoprotein IIb/IIa blocker has the lowest risk for immunogenicity?

Tirofiban (Aggrastat)

What is Eptifibatide (Integrilin)?

peptide inhibitor of fibrinogen binding to PGIIb/IIIa

infusion (up to 96 hrs), w/ ASA and heparin

acute coronary events and angioplast

what are adverse effects of Eptifibatide (Integrilin)?

bleeding (main risk), thrombocytopenia, less immunogenicity

What is Tirofiban (Affrastat)?

non-peptide inhibitor, renal elimination

infusion w/ heparin

What are adverse effects of Tirofiban (Affrastat)?

bleeding, bradycardia, dizziness

(lowest risk w/ immunogenicity bc non peptide/protein related)

What are the most important clotting factors?

X and II → common pathway

(hands on 10 and 2 when driving)

What is the mechanism of unfractionated heparin?

works w/ antithrombin III to inactivate clotting factors (intrinsic pathway)

provides platform for binding of thrombin to antithrombin III

How is unfractionated heparin given (UFH)?

IV (immediate onset) or subQ (1-2 hour delay); [not absorbed orally]

doesn’t cross placenta or BBB

dose dependent t1/2, may inc in cirrhosis and renal failure

Can Heparin be given in pregnancy?

yes - does not cross placenta, not in breast milk

What are the UFH monitoring parameters?

aPTT ; therapeutic ratio 1.5-2.5

What are indications for UFH?

venous thrombosis, pulmonary embolism, MI, coronary angioplasty

What is the antidote for UFH? (test question)

protamine sulfate

What toxicities do you have to worry about with UFH?

bleeding (major) → reversed w/ protamine sulfate (binds heparin)

heparin induced thrombocytopenia (HIT) → discontinue and give lepirudin, argatroban, or danaparoid

What is the antidote for heparin?

protamine sulfate

What is heparin-induced thrombocytopenia (HIT)?

immune rxn 5-10 days after initiation of heparin

antibodies to heparin and plt factor 4 → activates plts

discontinue immediately + give lepirudin/argatroban/danaparoid

(avoid LMWH and warfarin until thrombosis resolves)

What are examples of preparations of low molecular weight heparin (LMWH)?

enoxaparin (lovenox)

dalteparin (fragmin)

tinzaparin (innohep)

What is the mechanism of LMWH?

minimal effect on thrombin (IIa), lacks sequence to bind to antithrombin III

inhibits factor Xa

(more specific to factor X, less specific to factor II)

How is LMWH given?

subQ - fixed or weight adjusted dose once or twice daily

T1/2: 3-6 hrs

dec dose in renal failure and elderly (renal adjustment)

What do you have to monitor w/ LMWH?

monitoring typically not done- does not affect aPTT

can watch anti-factor Xa assay in renal failure and extremes of weight

LMWH toxicities

less bleeding than UFH; may cause HIT

What is Fondaparinux (Arixtra)?

shorter sugar chain than heparin

selective Xa inhibitor ; (factor X activity, no II at all); no monitoring

low incidence of HIT; not used in renal failure

What are indications for fondaparinux (arixtra)?

knee/hip replacement, pulmonary embolism, venous thrombosis

What are direct thrombin inhibitors?

based on Hirudin, a natural product from salivary glands of medicinal leech that inhibits thrombin directly

(primarily factor II activity)

monitor w/ aPTT

What are examples of direct thrombin inhibitors?

Lepirudin (Reflludan)- used in HIT; aPTT 1.5-2.5, IV, renal excretion

Bivalirudin (Angiomax)- coronary angioplasty; IV; renal excretion

Argatroban (Acova)- used in HIT; aPTT 1.5-3; hepatic excretion

What is the mechanism of Warfarin?

vitamin K antagonist; inhibits vit k epoxide reductase in a 2 step process

Prevents recycling of vit k -> prevent formation of new clotting factors

What vitamins should you never use in pregnancy?

fat soluble (A, D, E, K)

Can warfarin tx an acute clot?

no- doesn’t do anything to current circulating factors, only affects new factors

What is warfarin highly bound to?

albumin

(protein binding interactions can be a problem)

explain the onset of warfarin

delayed, loading dose doesn’t help, needs a bridge

anticoagulant effect begins in first 24 hrs, anti thrombotic effect in 5-7 days

initial hyper-coagulable state for first 24-48 hrs due to depletion of protein C (cover w/ heparin in high risk pats)

How is warfarin metabolized?

in the livaahhhh -

s-warfarin CYP2C9

R-warfarin CYP1A2 and 3A4

What would a 2C9 inhibitor do to warfarin levels?

inc levels (bc not metabolizing) → inc bleeding risk

Which is more potent- S or R warfarin?

S warfarin

How would a 3A4 inhibitor like grapefruit juice affect warfarin levels?

inc levels → inc bleeding risk

Can warfarin be used in pregnancy?

no- it crosses the placenta - Cl in pregnancy

not present in breast milk

What agents would cause dec action of warfarin?

inc uptake of vitamin K (found in green leafy vegetables, mayonnaise, oil, etc)

synthesis, function or clearance of clotting factors

what agents would cause inc action of warfarin?

CYP2C9 inhibition

protein binding interactions

abx that dec vit k (gut bacteria is important source of vit K)

low levels of factors due to dec liver function

being old

What are the monitoring parameters for warfarin?

PT and INR

What is the target INR value when you are monitoring for warfarin?

2-3.5

What high risk factors would require higher levels of warfarin?

mechanical heart valves and warfarin resistance

What patients would require a lower dose of warfarin?

warfarin sensitivity - if pt has CYP2CP alleles (much less efficient metabolism)

What are possible toxicities w/ warfarin?

bleeding, birth defects, skin necrosis in protein C or S deficiency

What INR range is associated w/ inc risk of a cranial hemorrhage w/ warfarin?

> 4

If a pt who takes warfarin has an INR is >5, what would you give to stop bleeding?

vitamin K1 (Phytonadione) PO, IV, or SubQ (aquamephyton, mephyton, konakion)

What is antidote for warfarin?

vit K - Phytonadione

What would you give for serious bleeding at any INR w/ warfarin?

fresh frozen plasma + vit k

What are some reasons why you would consider an alternative to warfarin?

highly diet dependent, requires frequent monitoring, multiple drug interactions (but it is easily reversible)

What does a higher INR mean?

blood is taking longer to clot indicating you have more warfarin around

What are some alternatives to warfarin?

Dabigatran etexilate (Pradaxa)

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

what is Dabigatran Etexilate (Pradaxa)?

oral direct thrombin inhibitor (only affects factor II)

prevents fibrinogen → fibrin and activation of factors V, VIII, XI, and XIII

How is Dabigatran Etexilate (Pradaxa) excreted?

renally; requires dose adjustment for CrCl

(does not require routine monitoring though)

What are adverse reactions of Dabigatran Etexilate (Pradaxa)?

bleeding, gastritis, dyspepsia

What is the reversal agent for Dabigatran Etexilate (Pradaxa) if bleeding occurs?

Idarucizumab (Praxbind)

What is Idarucizumab (Praxbind)?

monoclonal antibody targeted against dabigatran- indicated for rapid reversal of anticoagulation such as emergency surgery or uncontrolled bleeding

What are risks assoc. w/ Idarucizumab (Praxbind)?

inc coagulation risk (would need to add another anticoag)

adverse rxns: anaphylaxis, hypokalemia, delirium, constipation

What is Rivaroxaban (Xarelto)?

oral factor Xa inhibitor

no routine monitoring needed, renally excreted but no specific dosage adjustment

What are indications for Dabigatran (Pradaxa), Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa) ?

DVT, a fib, PE

What are adverse effects of Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa)?

bleeding and GI upset

What reverses bleeding w/ Rivaroxaban (Xarelto), Apixaban (Eliquis), and Edoxaban (Savaysa)?

prothrombin complex concentrate (PCC) or Adexanet Alfa (Andexxa)

What is Apixaban (Eliquis)?

oral factor Xa inhibitor, no routine monitoring needed

p-glycoprotein substrate; metabolized by CYP3A4 (watch for 3A4 inhibitor interactions)

What is Edoxaban (Savaysa)?

oral factor Xa inhibitor, no routine monitoring needed

renally eliminated (but if the kidney function is too good, it can be cleared too quickly making the drug less effective)

What pts should Edoxaban (Savaysa) NOT be used in?

A. fib pts w/ CrCl > 95 mL/min → inc risk of stroke

(reduce dose by 50% if CrCl is 15-50 mL/min)

What is Andexanet alfa (Andexxa)?

modified version of Factor Xa; designed to reverse bleeding due to apixaban and rivaroxaban (theoretically would work for edoxaban)

What are the risks w/ Andexanet alfa (Andexxa)?

secondary thrombosis- MI, ischemic stroke, VTE, death

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