Medications for Thromboembolic Disorders, Angina and ACS

Pharmacologic Approaches for thromboembolic Disorders

antiplatelet, anticlotting, thombolytics

Drugs that interfere with platelet aggregation =

antiplatelet medications

Drugs that interfering with the clotting cascade =

anticlotting medications, aka anticoagulants

Drugs that lyse thrombi =

thombolytics

Antiplatelet Agents / Anticoagulants:

Suppress thrombosis (thrombus formation). Do NOT "dissolve" clots

Antiplatelet Agents Are used to prevent or manage conditions such as:

DVT, Atrial fibrillation sequelae, Hypercoagulable states, Supplement post-thrombolytic therapy or stent plcement

Thrombolytics:

Lyse an existing thrombus

Thrombolytics Are used to treat conditions such as:

STEMI, ischemic stroke, PE

The P2Y12 receptor is the predominant __ receptor involved in the ADP-stimulated activation of the __ IIb/IIIa receptor

ADP, glycoprotein

ASPIRIN blocks

COX-1

CLOPIDOGREL blocks

P2Y12 receptor

Aspirin Mechanism

Irreversible inhibitor of COX-1 function for the life of the platelet

Platelets do not have a __ so they cannot make new COX -1

nucleus

For the __ of the platelet (7-10 days) COX-1 cannot function

life

No COX-1 --> no TxA2 produced via __ Cascade

AA

Aspirin blocks production of __

TxA2

Platelets have __ for pro-clotting signals

receptors

Platelets secrete __-clotting substances - many of which they also have __ for

pro, receptors

Aspirin class

Antiplatelet, NSAID

Aspirin indication

Secondary prevention of MI and ischemic stroke. Acute MI

Aspirin mechanism

antiplatelet; irreversibly inhibits COX (COX-1 > COX-2)

Inhibition of prostacyclin (PGI2) occurs when __ is blocked

COX-2

PGI2 inhibits platelets and __

vasodilates

Inhibiting PGI2 would partially __ the benefits of aspirin therapy

offset

if we keep the aspirin __-dose, we minimize the inhibition of __ , while still inhibiting TxA2

low, PGI2

Aspirin adverse effects

bleeding

Aspirin interactions

any combination of antiplatelet, anticoagulant and thrombolytic medications

Aspirin In Acute MI: 325 mg of non-enteric coated aspirin should be

chewed if an MI is strongly suspected

Avoid aspirin if __ is suspected, as it could be a __ stroke, and not ischemic

stroke, hemorrhagic

Why 325 mg?

loading dose, minimize the size of the clot

Clopidogrel Mechanism

blocks ADP receptor on platelets

Clopidogrel (Plavix®) class

Antiplatelet; ADP receptor antagonist

Clopidogrel (Plavix®) indication

ACS, prevent stroke, MI and death in patients with recent MI/stroke/PAD

Clopidogrel (Plavix®) mechanism

antiplatelet; irreversible ADP receptor antagonist

Clopidogrel (Plavix®) is what kind of drug

prodrug

What converts the prodrug to its active form?

CYP2C19

Clopidogrel (Plavix®) adverse effects

bleeding, dyspepsia, abdominal pain, diarrhea, rash

Clopidogrel (Plavix®) interactions

PPIs that inhibit CYP2C19, Cannabis also inhibits CYP2C19

Poor metabolizers will get __ or __ benefit from clopidogrel

little, no

Ultra-rapid metabolizers may experience more __ effects, including bleeding, from Clopidogrel

adverse

Anticoagulants are __ Alert Medications

High

In high-alert meds, the consequences of an error are clearly more __ to patients

devastating

warfarin prevents regeneration of active Vitamin __

K

active Vitamin K, necessary to make these 4 factors __ and __

activated, functional

Warfarin (Coumadin®) class

Anticoagulant; Vitamin K Antagonist

Warfarin (Coumadin®) indication

prevention of thrombosis associated with DVT/PE, prosthetic valves, atrial fibrillation. Tx of DVT/PE

Warfarin (Coumadin®) mechanism

anticoagulant; prevents active Vitamin K regeneration which reduces levels and functionality of activated vitamin-K-dependent clotting factors

Warfarin (Coumadin®) is how protein bound?

99%

How long does Warfarin (Coumadin®) take to become effective?

several days

What is the specific enzyme that Warfarin (Coumadin®) inhibits?

VKORC1

The Warfarin (Coumadin®) process occurs in what organ?

liver, in hepatocytes

Warfarin (Coumadin®) 2 genes that may affect metabolism

VKORC1 or CYP2C9

Warfarin (Coumadin ®) adverse effects

bleeding

Warfarin (Coumadin ®) contraindicated in

pregnancy

Warfarin (Coumadin ®) interactions

antiplatelet, anticoagulants, vitamin K, ANTIBIOTICS

Warfarin (Coumadin ®) antidote

Vitamin K, 4F-PCC

Warfarin Patient & Family Teaching: INR

get checked at frequency recommended by provider

Warfarin Patient & Family Teaching: avoid other drugs that

increase bleeding risk

Warfarin Patient & Family Teaching: tell other providers (including dentist)

that you are taking warfarin

Warfarin Patient & Family Teaching: safety precautions to avoid

falls, cuts, bruises

Warfarin Patient & Family Teaching: Food that contain vitamin K

maintain a consistent intake

Warfarin Patient & Family Teaching: wear a

medical alert bracelet

Heparin and enoxaparin increase activity of

antithrombin, which inhibits thrombin (Factor IIa) and Factor Xa

Enoxaparin preferentially inactivates

Factor Xa

Heparin (aka Unfractionated Heparin) class

Anticoagulant; unfractionated heparin (UFH)

Heparin (aka Unfractionated Heparin) indication

treatment/prevention of thrombosis, prevention of postop venous thrombosis, extracorporeal circulation, dialysis

Heparin (aka Unfractionated Heparin) mechanism

anticoagulant; increases antithrombin activity 1000x

Heparin binds antithrombin which then binds and inactivates

Factor Xa

Does Factor Xa come into direct physical contact with heparin molecule?

no

Antithrombin also binds and inactivates __/thrombin but IIa must also come into direct __ contact with heparin to be inactivated

IIa, physical

Heparin adverse effects

bleeding, heparin‐induced thrombocytopenia (HIT)

Heparin interactions

antiplatelet, anticoagulant medications

Heparin monitor

aPTT

Heparin antidote

Protamine sulfate

Heparin-induced thrombocytopenia (HIT)

Prothrombotic disorder caused by formation of antibodies to complexes of platelet factor 4 and heparin

In HIT: The antibodies bind to the PF4-heparin complexes on quiescent platelet surface and induce

platelet activation

In HIT: The activated platelets increase the __ and surface expression of __

release, PF4

In HIT: this creates

a positive feedback loop in which further release of PF4 promotes further platelet activation

In HIT: Platelet activation causes

release of procoagulant platelet microparticles, thrombosis, platelet consumption, and eventual thrombocytopenia

In HIT: Greatly increased generation of __, activation of inflammatory cells, and endothelial __ and activation follow

thrombin, injury

HIT: can cause both

venous and arterial thromboses, with devastating results

Enoxaparin (Lovenox®) (Low Molecular Weight Heparin) class

Anticoagulant; low molecular weight heparin (LMWH)

Enoxaparin (Lovenox®) indication

treatment and prevention of DVT, ischemic complications of acute MI, post-thrombolysis

Enoxaparin (Lovenox®) mechanism

anticoagulant; low-molecular weight heparin - increases anti-thrombin activity. Preferentially inactivates Factor Xa

LMWH is much shorter in __ than UFH

length

Enoxaparin (Lovenox®) adverse effects

bleeding

Enoxaparin (Lovenox®) interactions

antiplatelet agents, other anti-coagulants

Enoxaparin (Lovenox®) antidote

Protamine sulfate

Dabigatran Mechanism of Action

directly inhibits thrombin, preventing conversion of fibrinogen to fibrin

By inhibiting thrombin, this prevents activation of Factor __ which normally causes fibrin __

VIII, crosslinking

Dabigatran Etexilate (Pradaxa®) class

Anticoagulant; direct thrombin inhibitor

Dabigatran Etexilate (Pradaxa®) indication

prevention of systemic embolism and stroke in patients with atrial fibrillation, DVT/PE treatment and prophylaxis

Dabigatran Etexilate (Pradaxa®) mechanism

anticoagulant; direct thrombin inhibitor. Binds to free thrombin and thrombin bound to clots

Dabigatran Etexilate (Pradaxa®) is what kind of drug

prodrug; active in plasma and liver

Dabigatran Etexilate (Pradaxa®) contraindicated in eGFR

less than 30

Dabigatran Etexilate (Pradaxa®) adverse effects

bleeding, gastritis‐like complaints

Dabigatran Etexilate (Pradaxa®) interactions

P-glycoprotein inhibitors or inducers, anti-coagulants

Dabigatran Etexilate (Pradaxa®) contraindicated if active __ or __ prosthetic heart valve

bleeding, mechanical

P-glycoproteins pump drugs __ of cells; __ drug absorption

out, decreases

P-glycoprotein pumps Dabigatran Etexilate back into the __

intestine