Drugs Used In Coagulation Disorders I: Antiplatelet Agents Flashcards
What are the adverse effects of Aspirin?
Peptic ulcer
Bleeding
Does aspirin have good or bad oral absorption?
Good
How is aspirin administered?
Orally
Does aspirin have high or low plasma protein binding?
High
What does the 1st pass metabolism result in?
The formation of salicylic acid which is a reversible inhibitor
What is the dose of Aspirin when used for platelet aggregation?
50-200mg
What is the dose of aspirin when used for analgesic and antipyretic usages?
500mg
What are the clinical indications of Aspirin?
Pain, fever, inflammation
Primary or secondary prophylaxis of arterial thromboembolic diseases
Acute cases - unstable angina, MI, coronary angioplasty, stroke
What us dual anti platelet therapy?
ASA and P2Y12 receptor antagonist
What is the mechanism of action of aspirin?
Irreversible inhibition of COX in PLT
Resulting in decreased TXA2 and PGI2 synthesis
No platelet activation
What is the action of the COX enzyme?
Converts AA to TXA2
What are the activators of platelets?
ADP TXA2 Collagen 5-HT Thrombin
Name the thienopyridines
Ticlopidine Clopidogrel Prasugrel Ticagrelor Cangrelor
What is the mechanism of action of thienopyridines?
They are P2Y12 receptor non-competitive antagonists at the ADP receptor on platelets - they Decrease platelet aggregation
What are the clinical uses of the thienopyridines?
Cardio and cerebrovascular circulatory problems (TIA, stroke)
Dual anti platelet therapy: ASA +
P2Y12 receptor antagonist - decrease risk of
ACS and prevent coronary stent
thrombosis
What are the adverse effects of thienopyridines?
GI problems
Minor bleeding
Rarely Leuko and thrombocytopenia (especially Ticlopidine)
Which thienopyridines are most likely to cause thrombocytopenia and leukopenia?
Ticlopidine
Where are the thienopyridines activated?
In the liver
Are thienopyridines prodrugs?
Yes
Do thienopyridines have good or bad absorption?
Good
How are thienopyridines eliminated?
Renal and fecal elimination
Do thienopyridines have low or high protein binding?
High
What are the CYP2C19 inhibitors?
Omeprazol
Fluoxetine
Fluconazole
What is Clopidogrel inhibited by?
CYP2C19
What is the mechanism of action of Vorapaxar?
PAR-1 antagonist (antagonist of the thrombin receptor)
What is the clinical use of Vorapaxar?
MI (secondary prophylaxis)
Peripheral artery thrombosis (combination with aspirin)
Where is Vorapaxar metabolised?
The liver
What enzyme metabolised Vorapazar?
CYP3A
How is Vorapaxar administered?
Orally
What are the contraindications of Vorapaxar?
Bleeding
TIA
Stroke
What are the side effects of Vorapaxar?
Bleeding
What are the side effects of Abciximab?
Bleeding Thrombocytopenia Hypotension Bradycardia Nausea Vomiting
How is Abciximab administered?
IV
What is the metabolic half life of Abciximab?
Short - 30mins
What is the biological half life/duration of action of Abciximab?
18-24h
What are the clinical indications of Abciximab?
PCI in coronary syndrome
What is the mechanism of action of Abciximab?
GP IIb/IIIa receptor antagonist decreasing platelet aggregation
Monoclonal antibody
Irreversible antagonist
What is the mechanism of action of Eptifibatide and Tirofiban?
GPIIb/IIIa receptor antagonist decreasing platelet aggregation
Synthetic competitive inhibitor
What is the clinical use of Eptifibatide?
PCI in coronary syndrome
How are Eptifibatide and Tirofiban administered?
Continuous IV infusion due to their very short half life
What is the duration of action of Eptifibatide and Tirofiban?
2-4 hours
What is the mechanism of action of Dipyridamole and Cilostazol?
PDE inhibition (or adenosine uptake inhibition) leading to increased cAMP levels leading to activation of PKA
- vasodilation
- inhibition of platelet function
How are Dipyridamole and Cilostazol administered?
IV
What is the clinical indications of Dipyridamole and Cilostazol?
In combination with Warfarin as primary prophylaxis of thromboembolism in patients with prosthetic valves
What is the adverse effects of Dipyridamole and Cilostazol?
High does can lead to risk of coronary steal effect
When are anti-platelet drugs effective?
Only in arterial thrombosis
How do we measure PLT function?
Using bleeding time (not very accurate)
What does endothelial damage result in?
The exposure of sub-endothelial collagen and vWF
Where is Gp1b receptor located?
Platelet
What does Gp1b receptor on platelets bind to?
VWF
What is the result of Gp1b adherence to vWF?
Platelet activation
What are released from platelet granules?
ADP, 5HT, TXA2
What does ADP bind to?
P2Y12 receptors resulting in platelet aggregation
What is the result of 5HT?
Locally as a platelet aggregator and vasoconstrictor
What is the result of TXA2?
It causes platelets to change shape, causing activation and aggregation
Is COX2 always activated?
No, it is preferentially activated and expressed at sights of inflammation
What is the result of TXA2?
Vasoconstriction
What is the action of aspirin?
Irreversible covalent acetylation of cox
Irreversible inhibition of platelet production of TXA2 the entire life of the platelet
How should aspirin be administered in acute MI?
Aspirin should be chewed or crushed so that you achieve high blood concentrations quickly
What is the mechanism of action of thienopyridines?
Irreversibly blocking the ADP receptor (P2Y12) on platelets
What is a pseudo allergy?
Symptoms of allergies which are not IgE mediated
Which anti-platelet drug results in pseudo allergy?
Aspirin
When is pseudo allergy more likely?
In patients with a history of allergies
What is the cause of he aspirin induced pseudo Allergy?
Block of cox leading to increased leukotrienes
When do we use dual anti platelet therapy
- To reduce the risk of ACS and prevent coronary stent thrombosis
- To reduce the long term risk of cardiovascular events in patients with peripheral artery disease
- Acute ST elevation MI to prevent coronary artery thrombosis
- Prevention of Ischemic stroke in patients with atherosclerosis and known cerebrovascular disease
What is a side effect of ticlopidine?
Neutropenia and granuloytopenia
What should you do before putting a patient on ticlopidine and after the initiation of therapy?
CBC
What does GpIIb/IIIa bind to?
Fibrinogen
What is the result of GPIIb/IIIa and fibrinogen binding?
Activation and cross linking of platelets leading to the formation of the platelet plug
What type of antibody is Abciximab?
Monoclonal IgG
What is a major SE of GPIIb/IIIa inhibitors?
Drug induced thrombocytopenia
What should be monitored frequently in platelets using GPIIb/IIIa inhibitors?
Platelet count
What I the effect of anti platelet drugs on bleeding time
Prolonged bleeding time
What is the clinical significance of bleeding time?
Patients on anti platelet drugs
vWF disease
What does bleeding time measure?
Platelet function
What can be used as symtomatic tx of intermittent claudication?
Cilostazol due to its vasodilatory effects
Is there an antidote for Thienopyridines?
No
What is P2Y12?
It is a chemoreceptor for ADP
Gi coupled
Involved in platelet aggregation
What is PAR1?
Protease activated receptor
How is PAR1 activated?
Via serine proteases such as thrombin
Which coagulation factors are vitamin K dependent?
Factors II, VII, IX, X, proteins C and S.
What are the endogenous platelet activators?
TxA2 ADP Collagen 5HT Thrombin
Name the type of anti platelet drugs?
COX inhibitors P2Y12 Receptor antagonists-Thienopyridines GPIIb/IIIa receptor antagonists PDE inhibitors PAR-1 antagonists
Name the GPIIb/IIIa receptor antagonists
Abciximab
Eptifibatide
Tirofiban
Name the P2Y12 receptor antagonists
Ticlopidine Clopidogrel Prasugrel Cangreler Ticagrelor
Name the PAR1 antagonist
Vorapaxar
Name the PDE inhibitors
Dipyridamole
Cilostazole