PHARM I: EXAM #2 (HEME)

___________ irreversibly acetylates COX enzymes

Aspirin

Lifetime of a platelet?

7-10 days

______________:

Inhibits TXA2 for the life of platelet (7-10 days) (COX-1)

Inhibits PGI2 partially in the epithelium (COX-2)

Aspirin

Aspirin is _______________ (selective/non-selective)?

Nonselective

(**Acetylates both COX1 and COX2)

COX 2 inhibitors block __________ and **NOT TXA2

PGI2

______________:

- ASA – 7-10 days

- Ibuprofen, Diflunisal – 24 hrs

- Naproxen, Diclofenac, Indomethacin (48 hrs)

- Piroxicam – 72 hrs

- ***Reversible inhibitors - very little platelet inhibitory activity

NSAIDs

NSAIDs: time

- ASA – ______________

7-10 days

NSAIDs: time

- Ibuprofen, Diflunisal – ________

24 hrs

NSAIDs: time

- Naproxen, Diclofenac, Indomethacin – ________

48 hrs

NSAIDs: time

- Piroxicam – ________

72 hrs

NSAIDs: ____________ inhibitors - very little platelet inhibitory activity

Reversible

_________ side effect:

GI

- Dyspepsia

- GERD

- PUD

Bleeding – GI

- **Bruising up to 40% of patients

NSAIDs

________________________: Inhibit ADP binding to platelet receptors

-- P2Y1 receptor – pathway induces shape change and aggregation

-- P2Y12 receptor – inhibits cAMP-induced inhibition of platelet activation

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

______________________: Activation of both receptors types needed for complete platelet activation, blocking of just one limits platelet activation

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

ADP Receptor Blockers

Direct inhibition of fibrinogen binding to GPIIb/IIIa

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

_______________________: Interferes with binding of Von Willebrand factor

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

_________________________:

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

Antiplatelet Agents: ADP Receptor Blockers are _____________________ inhibition of platelet activation***

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

concentration dependent

______________________: are delayed 2-3 days for clinical effect MAX effect 8-11 days!!

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

What class of drugs are synergistic with ASA?

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

______________: prevent STROKE, MI, peripheral artery disease, angioplasty

Antiplatelet Agents: ADP Receptor Blockers

- Clopidogrel (Plavix®)

- Ticagrelor (Brilinta)

- Prasugrel (Effient)

(**-grel)

______________________: Prodrug

- Binds sulfur on P2Y12 receptor, synergistic with aspirin

Adverse effects:

***Thrombotic Thrombocytopenic Purpura (TTP)

Antiplatelet Agents: ADP Receptor Blockers

Clopidogrel (Plavix®)

______________: Prodrug

- Binds P2Y12 receptor, synergistic with aspirin

- Recommended over clopidogrel due to more platelet inhibition

Adverse effects

- Hypertension 8%

Antiplatelet Agents: ADP Receptor Blockers

Prasugrel (Effient®)

____________________:

- Not a prodrug, but has active metabolite

- Binds P2Y12 receptor, synergistic with aspirin

- Recommended over clopidogrel due to more platelet inhibition

Increased uric acid 22% (bad 4 GOUT)

Antiplatelet Agents: ADP Receptor Blockers

Ticagrelor (Brilinta®)

__________________ infusions (T1/2 30 min)

- Humanized monoclonal antibody

- Immediate onset, stays bound 18-24 hrs after infusion stopped, expensive

- Angioplasty with ASA and heparin, prevent restenosis

Adverse effects:

****Anaphylactic Rxn:

-- Could develop Neutralizing Abs

Antiplatelet Agents: Glycoprotein IIb/IIIA Blockers

Abciximab (ReoPro®)

____________________: inhibits the final pathway for platelet aggregation.

- Good for UA/NSTEMI, pt's undergoing PCI.

C/I: internal bleeding w/in30 days; major trauma/surgery, thrombocytopenia.

Antiplatelet Agents: Glycoprotein IIb/IIIA Blockers

- Tirofiban (Aggrastat®)

- Eptifibatide (Integrilin®)

- Abciximab (ReoPro®)

"TEA with IIb/III"

_______________________ infusions

- Peptide inhibitor of fibrinogen binding to PGIIb/IIIa, infusions up to 96 hrs

- Infusion, with ASA and heparin

- Acute coronary events and angioplasty

Adverse effects:

- Bleeding (10-12%)

- Bradycardia

- Dizziness

Antiplatelet Agents: Glycoprotein IIb/IIIA Blockers

Eptifibatide (Integrilin®)

___________________ infusions

- Non-peptide inhibitor, renal elimination

- Infusion, used with heparin

Adverse effects:

- Bradycardia

***LEAST Abs RXN!

Antiplatelet Agents: Glycoprotein IIb/IIIA Blockers

Tirofiban (Aggrastat®)

3 Antiplatelet Agent in order of least hypersensitivity --> worst

Tirofiban < Eptifibatide < Abciximab

______________: Antithrombin III suicide substrate of activated factors IIa >Xa >IXa >XIa >XIIa

Anticoagulants: Heparin

____________ provides platform for binding of thrombin to antithrombin.

Anticoagulants: Heparin

______________: Binds to & boosts/potentiates Antithrombin III's ability to inactivate Factor Xa, inactivates Thrombin (Factor IIa), inhibiting fibrin formation. Prevents new clot formation (however, does not dissolve existing clots!!!)

- Intrinsic pathway and Compliment pathway = Heparin (blocks II and X, IX, XI, XII)

Anticoagulants: Unfractionated Heparin (UFH)

____________: Extracted from porcine intestinal mucosa or bovine lung

(**Immunogenicity is higher from animals!)

Anticoagulants: Unfractionated Heparin (UFH)

______________: ***DOES NOT cross Placenta or BBB, not in breast milk, plasma protein bound.

(** It's too large to cross to fetus/breastfeeding infant!)

Anticoagulants: Unfractionated Heparin (UFH)

________________: Dose dependent t1/2, may ↑ in cirrhosis and renal failure

- IV or SQ only (***CANNOT be given orally, stomach will break down)

- ***aPTT monitoring test!

Anticoagulants: Unfractionated Heparin (UFH)

What test monitors Heparin?

aPTT

Monitoring parameters of ____________

aPTT (activated Partial Thromboplastin Time)

(aPTT ratio = patients aPTT / normal aPTT control)

Anticoagulants: Unfractionated Heparin (UFH)

_____________: Reversed by ***Protamine Sulfate (binds)

Anticoagulants: Unfractionated Heparin (UFH)

TOXICITY:

Anticoagulants: Unfractionated Heparin (UFH) can be reversed with _____________

Protamine Sulfate

Heparin-Induced Thrombocytopenia (HIT) is a toxicity expected with _______________.

Anticoagulants: Unfractionated Heparin (UFH)

If you see the following toxicity rxns, think _________________.

- Major Bleeding (reversed w/protamine sulfate)

- Heparin-Induced Thrombocytopenia (HIT)

Anticoagulants: Unfractionated Heparin (UFH)

_______________________: binds to & boosts/potentiates antithrombin III's ability to inactivate Factor Xa.

- Given SubQ as fixed or weight-adjusted dose once or twice daily

Chopped up Unfractionated Heparin (UFH) [Anticoagulants]

- Enoxaparin (Lovenox®)

- Dalteparin

Anticoagulants: Low Molecular Weight Heparin

(**-parin)

Do you use an aPTT test to monitor Low Molecular Weight Heparin?

No.

(**Heavier activity on X, less on II. IX, XI, XII = no aPTT.)

What test do you use to monitor Enoxaparin (Lovenox®) [AKA: Low Molecular Weight Heparin]?

A. aPTT

B. Anti-factor Xa assay

Anti-factor Xa assay

If a pt had a ****Heparin-Induced Thrombocytopenia (HIT) rxn to Unfractionated Heparin (UFH), what other drug should they AVOID?

Anticoagulants: Low Molecular Weight Heparin

(**-parin)

Which anticoagulant has the least risk for developing **Heparin-Induced Thrombocytopenia (HIT)?

Anticoagulant: Fondaparinux (Arixtra)

_______________ is a synthetic pentasaccharide based on antithrombin binding region of heparin.

- SubQ once daily, t1/2 17-21 hrs

- Not used in renal failure

- Low incidence of HIT

- Knee, hip replacement, pulmonary embolism, venous thrombosis

Anticoagulant: Fondaparinux (Arixtra)

_____________: Direct ***Factor Xa inhibitor (binds to & enhances antithrombin).

(**NO DIRECT EFFECT ON THROMBIN!)

Anticoagulant: Fondaparinux (Arixtra)

________________: Based on Hirudin, natural product from salivary glands of medicinal leech inhibit thrombin directly.

(****JUST WORKs ON FACTOR II - THROMBIN)

Anticoagulants: Direct Thrombin Inhibitors

________________: Based on Hirudin, natural product from salivary glands of medicinal leech inhibit thrombin directly.

- Lepirudin (Refludan®)

- Bivalirudin (Angiomax®)

- Argatroban (Acova®)

Anticoagulants: Direct Thrombin Inhibitors

(**-rudin, Argatroban)

What direct thrombin inhibitor is used in Heparin-Induced Thrombocytopenia (HIT), aPTT 1.5-2.5 X normal, IV, **renal excretion

Anticoagulants: Direct Thrombin Inhibitors

Lepirudin (Refludan®)

What direct thrombin inhibitor coronary angioplasty, IV, renal excretion?

Anticoagulants: Direct Thrombin Inhibitors

Bivalirudin (Angiomax®)

What direct thrombin inhibitor is used in Heparin-Induced Thrombocytopenia (HIT), aPTT 1.5-3 X normal, **hepatic excretion?

Anticoagulants: Direct Thrombin Inhibitors

Argatroban (Acova®)

What is special about Warfarin (Wisconsin Alumni Research Foundation) that other anticoags aren't?

(**-coum)

It is orally bioavailable!

______________ is more potent and it is metabolized by CYP2C9.

A. S-warfarin

B. R-warfarin

S-warfarin

Which anticoagulant is a Vitamin K antagonist?

Anticoagulants: Warfarin (Coumadin)

_____________ doesn't kick in immediately.

- It inhibits Vitamin K epoxide reductase rxn and ***prevents NEW clotting factors, but doesn't get rid of already made factors.

Anticoagulants: Warfarin (Coumadin)

_____________ has a ***DELAYED ONSET, but is great for long-term anticoagulant therapy.

Anticoagulants: Warfarin (Coumadin)

____________________: Initial hyper-coagulable state for first 24 -48 hrs d/t depletion of protein C.

- ****Cover with HEPARIN in high risk patients

Anticoagulants: Warfarin (Coumadin)

___________________:

- Given orally; 100% absorption

- T1/2 ~ 36 hours: steady state in 3-5 days

- Highly protein-bound (99%) to albumin

- Metabolized in LIVER

- S- warfarin CYP2C9

- R-warfarin CYP1A2 and 3A4

- Crosses placenta – C/I pregnancy***

- Not present in breast milk

Anticoagulants: Warfarin (Coumadin)

Warfarin is contraindicated in ____________ (fat soluble vitamins are needed by fetus)

pregnancy

What dietary guidance do pt's on Warfarin need?

They need a constant intake of Vitamin K

Things that affect pt's on ___________

1) Uptake and metabolism of oral drugs or vitamin K (green leafy vegetables)

2) Synthesis, function, or clearance of clotting factors

Anticoagulants: Warfarin (Coumadin)

Important source of Vitamin K?

gut bacteria

What two tests should you order for patients on Anticoagulants: Warfarin (Coumadin)?

PT & INR

What INR value are you shooting for in pt's with Warfarin?

2-3.5

(**Normal = 1)

___________________ sensitivity can be present in pt's with CYP2C9 alleles (much less efficient metabolism).

Anticoagulants: Warfarin (Coumadin)

Serious bleeding at any INR: GIVE these (2) things __________ + _____________.

Fresh Frozen Plasma (FFP) + Vitamin K

(**FFP has clotting factors. Gives them right back to pt...)

Pt was given too much Warfarin. When do you give Vitamin K1 (Phytonadione) PO, IV, or SubQ (AquaMEPHYTON, Mephyton, Konakion)?

INR > 5

***OTC Supplements that start with the letter G (eg, ginkgo biloba) + pt's on Anticoagulants: Warfarin (Coumadin) = ________________

Cranial Hemorrhage

Alternatives to ______________:

- Dabigatran etexilate (Pradaxa®)

- Rivaroxaban (Xarelto®)

- Apixaban (Eliquis®)

Anticoagulants: Warfarin (Coumadin)

______________: Prevents fibrinogen --> Fibrin, activation of factors V, VIII, XI, and XIII

Uses: DVT, PE, A-fib

- NO ROUTINE MONITORING NEEDED

- Alternative to Anticoagulants: Warfarin (Coumadin)

Anticoagulants: Dabigatran Etexilate (Pradaxa®)

What do you use to reverse Dabigatran Etexilate (Pradaxa®)?

Anticoagulants: Idarucizumab (Praxbind)

_________________: Oral factor Xa inhibitor

Reversible: Can be reversed with prothrombin complex concentrate (PCC)

Uses: DVT, atrial fibrillation, PE

- Alternative to Anticoagulants: Warfarin (Coumadin)

Anticoagulants: Rivaroxaban (Xarelto)

________________: Oral Factor Xa inhibitor

No routine monitoring needed

- Alternative to Anticoagulants: Warfarin (Coumadin)

Adverse Effects:

Metabolized by CYP3A4 (major)

Anticoagulants: Apixaban (Eliquis)