11 10 2014 Hematological agents Flashcards
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?
- prophylaxis (325mg/day)
- Unstable Angina
- acute myocardial infarction
- 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)
Ticlopidine
Type of drug?
Mechanism?
Thienopyridiens
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:
MI
Stroke
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
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
Pharmacokinetics of clopidogrel and prasugrel
prodrugs
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
USE:
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
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
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
How is UFH administered and when should you use Unfractionated heparin
parenterally – taken other than ingestion.
- not absorbed by GI tract
use when:
- unstable angina and NSTEMI
- acute MI after fibrinolytic therapy or extensive wall motion abnormality present
- 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
- 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
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?
- inhibition of platelet-bound factor Xa: more prominent anticoagulant effect
- less binding to plasma proteins and endothelial cells = more predictable bioavailability and longer half-life
- fewer bleeding complications
- 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
- used for post-operative prevention of thromoemblism : hip fracture, hip replacement, total knee replacement, major abdominal surgery.
- 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
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
Bivalriudin
synthetic peptide – directly inhibits thrombin
Short half life (25 min)
20% renal clearance
Inhibits platelet activation
FDA approved for use in coronary angioplasty
Argatroban
small synthetic derivative of arginine
- directly inhibits thrombin
First and ONLY ANTICOAGULANT INDICATED FOR BOTH PROPHYLAXIS AND HIT
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.
Mechanism of Warfin
blocks VKORC1 : Vitamin K reductase
inhibits biosynthesis of vitamin K depdent zymogens: Factors 2, 7, 9, 10 and Protein C/S
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
- Birth defects and abortion – contraindicated during pregnancy
- Skin necrosis
Dabigatran
Thrombin inhibitor
New direct oral anticoagulant
Reversible direct competative inhibitor of thrombin activity
Dabigatran pharmacokinetics and adverse effects:
prodrug
Low oral bioavailability
Renally cleared
Adverse effects: bleeding, GI disturbances
Rivaroxaban
Mechanism
Pharmacokinetics
Adverse effects?
Direct inhibitor of Factor X – direct anticoagulant
Oral bioavailability increases with food
Clearance: 70% liver via CYP3A4
Bleeding
tPA and urokinase pharmacology (pharmacology of firinolytic drugs
rapidly lyse thrombi by catalyzing the formation of plasmin from plasminogen.
Alteplase
human tPA manufactured by recombinant technology
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
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
