Anti-Platelets and Anti-Coagulants

Common NSAIDs

-Ibuprofen, Naproxen, Naproxen sodium, Indomethacin

Ketorolaac (parenteral NSAID)

(COX-2 agents are kinda in their own bracket)

-all increase risk of heart attack

primary vs secondary prophylaxis

1: given to prevent a stroke/MI

2: given to prevent ANOTHER stroke/MI

What was the first NSAID (the protypical agent)

Aspirin

What is the only NSAID with cardiac protection? Why?

Aspirin (primary vs secondary)

• it is an irreversible inhibitor of platelet aggregation

the others are reversible inhibitors

Aspirin MOA

-stimulates platelets by thrombin, collagen, ADP

-activation of platelet membrane phospholipids=liberation of arachidonic acid from membrane phospholipids

-arachidonic acid is converted to prostaglandin H2 (via COX-1)

-prostaglandin H2 is metabolized to thromboxane A2, which is released into plasma

-Thromboxane A2 promotes AGGREGATION process

-IRREVERSIBLE and rapid suppression of thromboxane A2 = plt aggregation is inhibited for the 7-10 days LIFE SPAN of platelets

ONLY ASPIRIN DOES THIS

Aspirin inhibits Thromboxane A2

Aspirin: Use/PK

-to prevent arteriolar clots (anti-coags prevent venous clots)

PK: after absorption it is hydrolyzed to salicylic acid via liver (reye syndrome: exposure to salicyclic acid)

Aspirin: dosing and indications

Dosing: 81-325mg EC TAKE WITH FOOD (nsaids and steroids)

Men: 45-79 to prevent AMI

Women: 55-79 to prevent ischemic stroke

Unisex: >80 only for hihg CV risks and no additional GI bleedings

Aspirin: adverse effects

Prolonged bleeding time: (increased risk of hemorrhagic stroke and GI Bleeding)

• ibuprofen: take within 2hrs before aspirin: antogonism for aspirins platelet inhibition (Take aspirin 1 hr BEFORE or 8 hrs AFTER ibuprofen)

CNS: Tinnitus

Reye syndrome: CNS effect (dont use in kids under 14)

P2Y12 ADP receptor inhibitors (Thienopyridine derivatives) Examples

1. Clopidogrel (Plavix)

2. Ticagrelor (Brilinta) ( reversible)

3. Prasugrel (Effient) most effective at plt aggregation

4. Ticlopidine (no longer available)

Cangrelor (IV infusion)-max inhibition of platelet aggregation within 2 mins (reversible)

P2Y12 ADP receptor inhibitors: MOA

MOA: Irreversible inhibition of ADP pathway of platelets; blocks the ADP receptor on platelets;

• no effect on prostaglandins

• inhibit binding of ADP to P2Y12 receptor on platelets → inhibit activation of GPIIb/IIIa receptors required for platelets to bind to fibrinogen and to each others

Which P2Y12 ADP receptor inhibitors binding is reversible

Ticagrelor and cangrelor

Which P2Y12 ADP receptor inhibitors binding is irreversible

Clopidogrel and Prasugrel

Which P2Y12 ADP receptor inhibitors require a loading dose?

The PO ones → for faster anti-platelet effect

Clopidogrel (Plavix): MOA/Use/Instructions/Hold

-with or without aspirin

-Max inhibition of platelet aggregation is 3-5 days

-duration of antiplatelet effect is 7-10 days

MOA: Prodrug: CYP450 system activates it via (CYP2C19)

• avoid other CYP450 2C19 inhibitors (eso/omeprozole)

• polymorphisms of cyp2c19 create a decreased clinical response (decreased efficacy→ gonna have a stroke/mi)

• inhibitors cause clopidogrel to not be metabolized (doesn’t become active) → we just pee it out

Hold for procedure: 5 days

Genetic polymorphism of CYP2C19

-decreases clinical response in CYP2C19

-decreased efficacy of clopidogrel (never gets activated)

-increases chance of CV or cerebrovascular event

Ticagrelor (Brilinta): MOA/dosing/Hold

MOA: PO Reversible ADP inhibitor

• BID, shorter duration but faster onset

• may inhibit new platelets that are infused

Dosing: BID. Give with loading dose. Take w/ 81mg of aspirin (higher dose will impair MOA)

• MAX inhibition of platelets aggregation is 1-3 hrs when given with loading dose

Hold for procedure: 5 days

Tricagrelor (Brilinta): Antidote

recombinant factor 7a suggested

Prasugrel (Effient): MOA/Dosing

MOA: irreversible inhibitor of ADP receptor

• most effective at platelet inhibition

Dosing: take with aspirin (81-325mg)

-max inhibition of platelet aggregation is 2-4hrs

-hold for procedure: 7 days

Prasugrel (Effient): ADR/Interactions/Hold/Antidote

ADR: BLEEDING (worse of the 3 p2y12adp inhibitors) black box warning

• Contraindicated in pts w/ prior TIA or stroke (not primary prophylaxis)

Drug Interactions: any other drug that increases leeding risk (no NSAIDs or warfarin. only tylenol allowed (not antiplatelet activity))

Hold: 7 days (like aspirin)

Antidote: platelet infusion

Adverse effects of PP2Y12 ADP receptor inhibitors

• Bleeding (black box): tricagrelor, prasugrel, cangrelor

• Decreased efficacy when used with aspirin >100mg (Black box): Ticagrelor (T=too much aspirin)

• prolonged bleeding time

• thrombocytopenia

• TTP (thrombotic thrombocytopenic purpura)

Glycoprotein IIb/IIIa inhibitors: Use

1. Eptifibatide (Integrillin)

2. Tirofiban (Aggrastat)

• use for pt with acute coronary syndromes, along with heparin and aspirin

-most potent

Glycoprotein IIb/IIIa inhibitors: MOA

MOA: Target platelet IIb/IIIa receptor complex - final pathway for platelet aggregation

-given IV

-adverse effect: Bleeding

Anti-Platelet Potencies

most to least potent

1. GP IIb/IIIa inhibitors >

2. Thienopyridine derivatives (effient, Brilinta, Plavix) >

3. aspirin

Pregnancy categories of anti-platelet drugs

Category B:

-Prasugrel, Eptifibatide, Tirofiban, Clopidogrel

Category C:

-Aspirin (sometimes), ticagrelor

How long to hold for procedure (anti-platelets)

Clopidogrel, Ticagrelor = 5 days

Prasugrel = 5-7 days

Aspirin = 7 days

Warfarin (Coumadin): MOA

MOA: Inhibits Vitamin K dependent, hepatic coagulation factors: 2, 7, 9, 10, & protein C and S

• peak effects delayed for 72-96 hrs (may need to bridge with another anticoagulant)

→ results in production of clotting factors with diminished activity

can be used with heparin for bridging

metabolized by CYP450 2C9 = many drug interactions

Warfarin: PK/dosing

no loading dose

half life: 40-72 hours

Warfarin: Pregnancy Category/Antidote

Pregnancy Category X

• sometimes used in breastfeeding women

• can cross into placenta → hemorrhagic disorders

(If pregnant and needs anticoagulant - GIVE HEPARIN)

Warfarin: Monitoring

-Monitor INR weekly for first few weeks, then every 2 (adjust dose as needed)

-INR= aim for the middle of the range

-Higher INR → indicates higher level of anticoagulation

-hold: 5 days (might bridge with injectable)

watch for drug interactions

-maintain consistent amount of vitamin K in diet

Warfarin: adverse reactions/Warnings

Adverse reactions: bleeding and many more

• Use with Vit K may decrease anticoagulant effect (also used as antidote)

-purple toe syndrome (caused by cholesterol emboli from plaques)

• DO NOT USE W/ NSAIDS

-Use acetaminophen (Tylenol) for pain/fever

Dabigatran (Pradaxa): MOA/Use/CI

MOA - direct thrombin inhibitor (factor 2a)

Use: For reducing risk of stroke and systemic embolim in pts w/ non valvular Atrial fibrillation; used in place of warfarin

CI: contraindicated in pts with mechanical prosthetic heart valves

How long to hold Dabigatran (Pradaxa) for procedure?

24-72 hours

Dabigatran (Pradaxa) reversal agents

Idarucizumab (Praxbind) and activated charcoal

Dabigatran ADR/Precautions

ADR: contains tartaric acid → causes reflux (pts will take with food and proton pump inhibitors)

Precautions: if dose is missed, the effectiveness can wane within 15 minutes of the missed dose

Direct oral Factor Xa inhibitors

-rivaroxaban (Xarelto)

-Apixaban (Eliquis)

-Edoxaban (Savaysa)

all are PO agents

Direct oral factor Xa inhibitors: MOA/Indications

MOA: inhibits factor Xa

• (→reduces production of thrombin from prothrombin)

Indicated: Used in place of warfarin or LMWH to prevent venous thrombosis after hip/knee replacement surgery

• Approved to prevent stroke in pts w/ afib

In what situation would you reduce dosages of a direct oral factorXa inhibitor?

when taking with other P=pg inhibitors such as clarithromycin, verapamil, and amiodorone

Direct oral factor 10a inhibitors: ADR & reversal agent

ADR: bleeding

Reversal agent: Andexxa (coagulation factor X)

Rivaroxaban (Xarelto): CYP isoenzyme: MOA

metabolized by CYP 3A 4/5 and CYP 2J2 isoenzymes to inactive metabolites

Apixaban (Eliquis): CYP

-metabolized by CYP 3A4, with CYP enzymes 1A2, 2C8, 2C9, 2C19, 2J2 all sharing minor metabolic roles

Xarelto and Eliquis should be avoid when taking

-strong P-gp and CYP 3A4 inducers (phenytoin, carbamazepine, rifampin, St. John wort)

-it can reduce the efficacy of the factor 10a inhibitors

Heparin: MOA and reversal agent

-injectable, rapid-acting, interferes with formation of thrombi

MOA: binds to antithrombin III→ rapid inactivation of coagulation factors (Thrombin (F2a) and 10a) → prevents fibrin formation

Heparin reversal agent

reversal agent: protamine

Heparin: Uses and pregnancy category

-treats acute venous thromboembolism (DVT, PE)

-used before operation and in pt's with acute MI

-pregnancy Category C (anticoagulant of choice)

How do you monitor Heparin?

activated partial thromboplastin time (aPTT)

• (UFH only, not LMWH bc they only inhibit F10a

-anticoagulant effect: IV=minutes, SC=1-2 hrs

What is the traditional heparin therapy?

unfractionated heparin SC or IV, obtained frmo pock intestinal mucosa

LMWH (Low molecular weight heparins) Examples

Dalteparin (Fragmin)

Enoxaparin (Lovenox)

LMWH MOA and administration route

inhibition of Xa by antithrombin (not long enough to inhibit thrombin)

Route: SQ administration

benefits of using a LMWH compared to other antiplatelet options

-equal efficacy

-increased bioavailability from SQ site (anticoagulant effect=4 hrs)

-less frequent dosing (longer half life than UFH)

LMWH/heparin monitoring & ADR

Monitor factor Xa levels for renal impairment, pregnancy, obesity

-ADR: Bleeding, thrombocytopenia (less than UFH), hypersensitivity (allergic rxn): anaphylaxis, alopecia, cataracts, osteoporosis, urticarial, chills fever (with long term therapy)

-avoid in alcohol use disorder and some surgeries (brain, eye, spinal cord)

HIT (Heparin induced thrombocytopenia)

-systemic hypercoagulable state (1-4% of pts)

-treated with UFH x7 days

-surgical pts have highest risk

-do platelet counts frequently

Argatroban (acova)

-anticoagulant derived from L-arginine used in prophylaxis and to treat HIT, used during PCI in pts who have risk for HIT

-direct thrombin inhibitor

Argatroban (acova) monitoring and ADR

-monitor with aPTT, hemoglobin, hematocrit

-anticoagulant effects are immediate

-ADR: bleeding

Bivalirudin (Angiomax)

-anticoagulant used to treat HIT

-direct, selective thrombin inhibitor

Fondaparinux

-synthetically derived pentasaccharide anticoagulant that selectively inhibits factor Xa

-SC injection

-used to treat DVT, PE, prophylaxis of venous thromboembolism (in orthopedic and abdominal surgery)

-ADR: BLEEDING

Anticoagulant Pregnancy Categories

Category B: Heparin, LMWH, argatroban, bivalirudin, apixiban

Category C: Dabigatran, rivaroxaban

Category X: Warfarin

How long to hold for procedure - anticoagulants

Heparin - 4-6 hours

LMWH - 12-24 hours

Dabigatran, rivaroxaban, apixiban = 24-72 hrs

Warfarin - 5 days

Antiplatelets

-Aspirin, Clopidogrel, Ticagrelor, etc

-Used for ARTERIAL clots, due to platelet aggregation

-prevent platelet aggregation

Anti-coagulants

-Warfarin, DOACs

-used for clots in veins or atria of heart due to fibrin meshes of RBCs

-useful in VENOUS thrombosis

Thrombolytics (fibrinolytic drug)

-break up and DISSOLVE the thrombus/clot (Clot busting)

-Enzymes that kick off process of breaking down proteins (fibrins) that form clot (convert plasminogen to plasmin)

-work better the faster they are started after clot formation

-increased local thrombi may occur: given aspirin or heparin to prevent this

-Alteplase (t-PA): derived from human melaona cells, recombinant DNA technology, Reteplase, tenecteplase

Thrombolytic agents ADR

-hemorrhage (they don't distinguish between unwanted thrombus and beneficial hemostatic plug)

-do not use in pregnancy, pts with healing wounds, or pt with hx of cerebrovascular accident, brain tumor, head trauma, intracranial bleeding, and metastatic cancer

Protamine sulfate MOA

-antagonizes the anticoagulant effects of heparin

-derived from fish sperm or testes

-positively charges protamine and negatively charged heparin=stable complex without anticoagulant effects

Protamine sulfate ADR

-allergy, dyspnea, bradycardia, hypotension

Vitamin K (Phytonadione)

-helps stop bleeding due to warfarin

-PO and IV preferred (Also SC)

-slow response (24hrs to lower INR)

-FFP (fresh frozen plasma) is faster

Idarucizumab (praxabind)

-used to reverse bleeding caused by dabigatran

-IV admin in emergencies

-ADR: thrombosis

Factor 10a (Xa)

-recombinant modified human protein

-IV

-used to reverse apixaban or rivaroxaban

-NOT approved for edoxaban reversal

-ADR: arterial and venou thromboembolism, MI, ischemic stroke, cardiac arrest, sudden death