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Flashcards in 11 10 2014 Hematological agents Deck (43):
1

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)

2

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

3

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)

4

Clopidogrel (Plavix)
Prasugrel ( Eficient)
Ticlopidine

Type of drug?
Mechanism?

Thienopyridiens

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

= inhibits platelet aggregation!

5

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

Patients who have had a previous:
MI
Stroke
Peripheral vascular disease

6

Sideeffects of clopidogrel and Prasugrel

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

Bleeding, dyspepsia (indigestion), diarrhea

Rare:
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

7

Pharmacokinetics of clopidogrel and prasugrel

prodrugs
Metabolized by CYP 450

* prasugrel is metabolized quicker

8

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


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

9

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

monoclonal antibody directed against GPIIB/IIIA complex.

Approved for coronary angioplasty and acute coronary syndrome (ACS)

10

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

11

Tirofiban -- exact structure/ form

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

12

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

13

dipyridamole

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

14

Unfractionated Heparin

mechanism?

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

15

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

16

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

17

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

18

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

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

19

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

Enoxaparin, Dalteparin Tinzaparin

* the "parins"

20

Mechanism of LMWH?

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

21

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

22

LMWH is effective for what?

-Preventing deep venous thrombosis during post-operative period

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

23

When should UFH be given instead of LMWH

-prevention of venous thrombosis
-Treatment of angina

24

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

25

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

26

Mechanism of Fondaparinux

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

27

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

28

Contraindications to using Heparin?

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

29

Who are the direct thrombin inhibitors?

Hirudin, Lepirudin, Bivalirudin, argatroban

30

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

31

Hirudin

Directly inhibits thrombin
recombinant form of desirudin -- 65 amino acid protein isolated from medical leeches (hirudo medicinal is)

Most potent known inhibitor of thrombin

Does not cause thrombocytopenia.

Approved for:
prevention of deep vein thrombosis after elective hip arthroplasty

32

Bivalriudin

synthetic peptide -- directly inhibits thrombin
Short half life (25 min)
20% renal clearance
Inhibits platelet activation
FDA approved for use in coronary angioplasty

33

Argatroban

small synthetic derivative of arginine
- directly inhibits thrombin

First and ONLY ANTICOAGULANT INDICATED FOR BOTH PROPHYLAXIS AND HIT

34

Warfin
Pharmacokinetics

Indirect anti-coagulant.

Plasma concentration peaks about 2-8 hr afar an oral dose

99% bound to plasma proteins (albumin)
- Half-life in plasma is 25-60 hrs

Extent of coagulation has to be measured via prothrombin time ( extrinsic ) PT.

35

Mechanism of Warfin

blocks VKORC1 : Vitamin K reductase

inhibits biosynthesis of vitamin K depdent zymogens: Factors 2, 7, 9, 10 and Protein C/S

36

Adverse effects of warfin

-1. bleeding
If bleeding arises during Warfin treatment, it can be reversed within hours with the addition of vitamin K. OR MORE QUICKLY WITH PLATELET TRANSFUSION

2. Birth defects and abortion -- contraindicated during pregnancy

3. Skin necrosis

37

Dabigatran

Thrombin inhibitor
New direct oral anticoagulant

Reversible direct competative inhibitor of thrombin activity

38

Dabigatran pharmacokinetics and adverse effects:

prodrug
Low oral bioavailability
Renally cleared

Adverse effects: bleeding, GI disturbances

39

Rivaroxaban

Mechanism
Pharmacokinetics
Adverse effects?

Direct inhibitor of Factor X -- direct anticoagulant

Oral bioavailability increases with food
Clearance: 70% liver via CYP3A4

Bleeding

40

tPA and urokinase pharmacology (pharmacology of firinolytic drugs

rapidly lyse thrombi by catalyzing the formation of plasmin from plasminogen.

41

Alteplase

human tPA manufactured by recombinant technology

42

contradictions to treatment with tPA

Absolute constraints:
prior intercranial hemorrhage
Ischemic stroke (3 months)
Suspected aortic dissection
Active bleeding
Significant closed head trauma

Relative constraints
uncontrolled hypertension
Traumatic or prolonged CPR or major surgery within 3 weeks

43

Aminocaprioc acid:

what is it?
Pharmacokinetics?
Clinical uses?
Adverse effects?

Fibrinolytic inhibitor
- synthetic inhibitor of fibrinoylsis

Orally or parenterally
Binds plasmin and plasminogen and interferes with function

clinical uses:
-Adjunct therapy to hemophilia
-bleeding from Fibrinolytic therapy
- postsurgical gastrointestinal bleeding and bladder
- Hemorrhage secondary to radiation

Adverse effects:
Intravascular thrombosis from inhibition of plasminogen.
Hypotension
Myopathy
Abdominal discomfort
Diarrhea
nasal stuffiness