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Flashcards in 11 10 2014 Hematological agents Deck (43)
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Aspirin Mechanism

Why do you not want to give a high dose of Aspirin?

Why is aspirin not a complete anti-thormbotic agent?

irreversible acetylation of COX-1 (essential enzyme for TXA2 production)

Depending on dose it usually inhibits platelet COX-1 (higher doses can inhibit Cox-1 in endothelial cells -- which you don't really want because it will impaired Prostaglandin production -- they are antagonists of TXA2)

Only inhibits thrombosis via COX-1… other mechanisms of thrombosis are not affected (ex ADP)


Clinical uses of Aspirin

A pro to using Aspiring

However… what should it not be used as?

1. prophylaxis (325mg/day)
2. Unstable Angina
3. acute myocardial infarction
4. History of myocardial infarction
* prevention of secondary events

Reduces incidence of future fatal and nonfatal coronary events.

HOWEVER, it is not clear if it should be used as PRIMARY prevention


Adverse effects of Aspirin

- GI bleed
- increased risk of hemorhagic stroke
-increased incidence of peptic ulcer disease
- may also exaggerate gout symptoms (since it is excreted by kidney it competes with uric acid)


Clopidogrel (Plavix)
Prasugrel ( Eficient)

Type of drug?


Irreversibly inhibit the binding of ADP to its receptor on platelets -- inhibits GPIIb/IIIa activation

= inhibits platelet aggregation!


When do you use clopidogrel (Plavix) or Prasugrel (Eficient)

Patients who have had a previous:
Peripheral vascular disease


Sideeffects of clopidogrel and Prasugrel

A downfall to using these drugs incase someone needs surgery for acute coronary syndrome?

Bleeding, dyspepsia (indigestion), diarrhea

Severe neutropenia and thrombotic thrombocytopenic purport (which is why ticlopidine is limited)

Irreversible platelet inhibitors: ned to wait a period of several days to allow platelet function to return in order to prevent preoperative bleeding complications


Pharmacokinetics of clopidogrel and prasugrel

Metabolized by CYP 450

* prasugrel is metabolized quicker


mechanism of Abciximab, eptifibataide, and tirofiban?

What are they used commonly for?

Reversible Glycoprotein IIB/ IIIA receptor antagonists

_bind to receptor and prevent them from being activated when platelet binds to vWF.

Prevents binding of fibrin
= prevents formation of 3D platelet plug

improve outcomes of patients undergoing percutaneous coronary interventions and in high-risk acute coronary syndromes


Abciximab -- exact structure/form
What is approved for?

monoclonal antibody directed against GPIIB/IIIA complex.

Approved for coronary angioplasty and acute coronary syndrome (ACS)


Eptifibatide -- exact structure/ form

synthetic peptide of the detail chain of fibrinogen
-- mediates binding of fibrinogen to the receptor

- drug occupies receptor and inhibits binding of fibrin


Tirofiban -- exact structure/ form

non-peptide analog of the main recognition sequence of GPIIb/ IIIa receptors


Pharmacokinetics of Glycoprotein IIb/IIIa receptor antagonists?

all must be administered through IV

Abciximab has a short plasma half life so it can be reversed by discontinuing drug.

Other two have a longer half life and may continue to inactive transfused platelets even after discontinuation



given to patients intolerable of aspirins but it is not as effective as aspirin

Platelet Inhibitor
- inhibits phosphodiesterase PDE5 -- increase cAMP and blocks platelet response to ADP


Unfractionated Heparin


Specific from blocking thrombin

-associates with anti-thrombin in circulation
recall that anti-thrombin (AT) naturally inhibits action of thrombin (clotting factor)

- reduces thrombin's ability to make fibrin
- AT- heparin inactivates factor 10


How is UFH administered and when should you use Unfractionated heparin

parenterally -- taken other than ingestion.
- not absorbed by GI tract

use when:
1. unstable angina and NSTEMI
2. acute MI after fibrinolytic therapy or extensive wall motion abnormality present
3. Pulmonary embolism or deep venous thrombosis


What are side effects of heparin?

How can you treat an overdose of UFH?

bleeding and heparin induced thrombocytopenia (HIT)

Protamine Sulfate: forms a stable complex


Heparin induced thrombocytopenia (HIT)

Dangerous form:
-immune mediated condition due to Heparin-platelet complex.
- causes bleeding and thrombosis (paradoxically) -- results in platelet activation, aggregation and clot production
-platelet falls drastically and is not dependent on the dose

Immediate cessation of heparin

If patient has HIT do not give them UFH or Low molecular weight heparins


Some pharmacokinetics of UFH
- half-life
- monitor?
- bind to plasma proteins?

short half-life
bioavailability varies on individual
need to check aPTT or Anti-Xa
Highly bound to plasma proteins


Low molecular weight Heparins (LMWH):
(names -- 3 drugs)

Enoxaparin, Dalteparin Tinzaparin

* the "parins"


Mechanism of LMWH?

preferentially inactivates factor 10a (need larger molecule to inactivate thrombin)


Advantages of LMWH over UFH?

1. inhibition of platelet-bound factor Xa: more prominent anticoagulant effect

2. less binding to plasma proteins and endothelial cells = more predictable bioavailability and longer half-life

3. fewer bleeding complications

4. Lower incidence of immune-mediated HIT

Has a longer half life
Can be administered subcutaneously-- injection once or twice a day without frequent blood monitoring
excreted by kidneys


LMWH is effective for what?

-Preventing deep venous thrombosis during post-operative period

- treatment of acute venous thromboembolic disease and acute coronary syndromes.


When should UFH be given instead of LMWH

-prevention of venous thrombosis
-Treatment of angina


Fondaparinux (Arixtra)
- What it is and what it targets?
- clinical uses?

synthetic pentasaccharide that specifically inhibits factor Xa
synthetic factor Xa inhibitor

- prevention of venous thormboembolism following surfer; initial treatment of DVT and Pulmonary embolism


Advantage of Fondaparinux

Both UFH and LMWH bind to platelet factor 4 = HIT
* Fondaparinux does not bind to platelet factor 4
= NO Heparin Induced Thromocytopenia!!!
* does not require monitoring by aPTT


Mechanism of Fondaparinux

binds to AT3 ( antithrombin 3) with high affinity = greatly increases AT's ability to inactivate factor 10a


Clinical use of Fondaparinux

1. used for post-operative prevention of thromoemblism : hip fracture, hip replacement, total knee replacement, major abdominal surgery.

2. Initial treatment for DVT and pulmonary embolism


Contraindications to using Heparin?

-hypersensitivity to the drug
- Actively bleeding
- genetic bleeding disorders ( Hemophila)


Who are the direct thrombin inhibitors?

Hirudin, Lepirudin, Bivalirudin, argatroban


Mechanism of direct thrombin inhibitors?
- advantage over heparin?

They bind directly to thrombin. Benefit over Heparin is that Heparin - AT complex can only bind circulating thrombin and not thrombin already in clot.

Since Direct thrombin inhibitors don't rely on AT, they inhibit both circulating and clot-bound thrombin.

Do not cause thrombocytopenia and can be used in HIT patients