Lecture 12- Anti-platelet and fibrinolytic drugs

Question 1

Thrombus

Answer 1

• a clot adhered to vessel wall

Question 2

Embolus

Answer 2

• intravascular clot distal to site of origin

Question 3

Thromboembolic diseases are common

Answer 3

· deep vein thrombosis (DVT) and pulmonary embolism (PE)

· consequence of atrial fibrillation (AF)

· transient ischaemic attacks (TIA)

· ischaemic stroke

· myocardial infarction (MI

Question 4

arterial thrombosis

Answer 4

• Usually forms at site of atherosclerosis following plaque rupture
• Lower fibrin content and much higher platelet content than venous thrombosis

Question 5

Venous thrombosis

Answer 5

• Associated with stasis of blood and or damage to the veins – less likely to see endothelial damage
• High red blood cell and fibrin content, low platelet content evenly distributed

Question 6

healthy endothelium

Answer 6

‘resting platelets’

• Prostacyclin (PGI2) produced and released by endothelial cells- inhibits platelet aggregation
  
  • PGL2 binds to platelet receptors  increase [cAMP] in platelets
  • Increased cAMP  decreases calcium- preventing aggregation
  • Decrease in platelet aggregatory agents
  • Stabilises inactive GPIIb/IIIa receptors

Question 7

what inhibits platelt aggregation

Answer 7

prostacylin (PGI2) produced by healthy endothelium

Question 8

Platelet lifespan​

Answer 8

8-10 days

• 10% replaced each day turnover

Question 9

Platelet activation and aggregation

Answer 9

1) Platelet adhesion

• Damage to vessel wall (endothelium)
• Exposure of underlying tissues
• Resting platelets adhere to collagen via vWF/receptors

2) Platelet activation

• platelets secrete granules (ADP, thromboxane A2, serotonin, platelet activation factor (PAF) and thrombin) to become activated and activate other platelets

3) Platelet aggregation

• Cross linking of platelets to form platelet plug
  
  • activation and aggregation ultimately through GPIIb/IIIa receptors and fibrinoge
  • increase calcium and decrease cAMP in platelets
  • increase platelet aggregation
  • cascade and amplification from platelet to platelet
• Mediating factors
  • Thromboxane A2
  • Von Willebrand’s factors
  • Fibrinogen
  • Collagen
  • ADP

Question 10

Reduction of pathological platelet aggregation essential in

Answer 10

reducing cardiovascular events and reducing mortality

Question 11

Therapeutic agents available disrupt various stages of signalling cascade

Answer 11

• Platelet rich “white” arterial thrombi – antiplatelet and fibrinolytic drugs used
• Lower platelet content, “red” venous thrombi – parenteral anticoagulants heparins etc. and oral anticoagulants warfarin etc. (session 11)
• A combination of both may be used in some patients often
  in secondary prevention – targeting multiple sites and mechanisms of thromboembolic cascades

Question 13

name the antiplatelet classes

Answer 13

• Cyclo-oxygenase inhibitors
• ADP receptor antagonists
• Phosphodiesterase inhibitors
• glycoprotein IIb/IIIa inhibitors

Question 14

clot busters

Answer 14

fibrinolytic agents - mediate thrombolysis

Question 15

name a drug under the class cyclo-oxygenase inhibitor

Answer 15

aspirin

Question 16

uses of aspirin (cyclo-oxygenase inhibitor)

Answer 16

• Antiplatelet
  
  • Atrial fibrillation
  • Secondary prevention pf stroke and TI
  • Secondary prevention for acute coronary syndrome
  • Post primary percutaneous coronary intervention and stent to reduce ischaemic complications
  • NSTEMI/STEMI (initial once only 300 mg loading dose- chewable is best)
  • Acute ischaemic stroke- 300mg daily for 2 weeks

Question 17

Pharmacokinetics Aspirin (Cyclo-oxygenase inhibitor)

Answer 17

• Absorbed by passive diffusion
• Hepatic hydrolysis to salicylic acid (active form)
• COX-1 polymorphism results in lack of efficacy in some

Question 18

mode of action of aspirin

Answer 18

• aspirin inhibits COX-1
  
  • COX-1 mediates arachidonic acid convertion to Prostaglandin H2 (PGH2) which then becomes–> thromboxane A2 (TXA2)
  • thromboxane A2 (TXA2) potent platelet aggregating agent
• therefore reduction in platelet aggregation
• irreversible

Question 19

low dose aspirin

Answer 19

Daily low-dose aspirin is a blood thinning medicine- 75mg

Question 20

Adverse drug response: aspirin

Answer 20

• GI irritation (gastric protection required for long term use in at risk pts (PPIs needed)
• GI bleeding (peptic ulcer)
• Haemorrhage (stroke)
• Hypersensitivity to aspirin

Question 21

Contraindications: aspirin

Answer 21

• Reyes syndrome – avoid <16 years
  
  • Causes liver disease and brain damage
• Hypersensitivity to aspirin
• 3^rd trimester- premature closure of ductus arteriosus

Question 22

Drug-drug interaction: aspirin

Answer 22

Caution- other antiplatelets and anticoagulants (additive/ synergistic action)

Question 23

name 3 drugs under the class ADP receptor antagonist

Answer 23

• Clopidogrel
  
  • monotherapy when aspirin is contraindicated
  • NSTEMI- pts -3 months
  • STEMI pts- up to 4 weeks
• Prasugrel- with aspirin in ACS patients (undergoing PCI) for up to 12 months)
• Ticagrelor - with aspirin in ACS patients (undergoing PCI) for up to 12 months)

Question 24

when are ADP receptor antagonists used e.g. clopidogrel

Answer 24

• MI
• ischaemic stroke

Question 25

Mode of action

Answer 25

• ADP receptor antagonist- inhibits binding of ADP to P2Y₁₂ receptor
• Inhibiting activation of GPIIb/IIIa receptors (independent of COX pathway)

Question 26

clopidogrel pharmacokinetics

Answer 26

• Irreversible inhibitor of P2Y12
• Prodrugs- need hepatic metabolism to produce active metabolites
• Slow onset of action without loading dose
• Inter-individual variability in antiplatelet action

Question 27

prasugrel pharmacokinetics

Answer 27

• Irreversible inhibitors of P2Y₁₂
• Prodrugs- need hepatic metabolism to produce active metabolites
• rapid onset

Question 28

Ticagrelor pharmacokinetics

Answer 28

Acts reversibly at different sites to clopidogrel and has active metabolites

Question 29

Adverse drug response: ADP receptro antagonists e.g. clopidogrel

Answer 29

• Bleeding
• GI upset- dyspepsia and diarrhoea
• thrombocytopenia

Question 30

Contraindications ADP receptor antagonists e.g. clopidogrel

Answer 30

• caution in high bleed risk pts with renal and hepatic impairment
• clopidogrel needs stopping 7 days prior to surgery

Question 31

Drug-drug interaction: ADP receptor antagonist e.g. clopidogrel

Answer 31

• clopidogrel requires CYPs for activation
  
  • CYP inhibitors: omeprazole, ciprofloxacin, erythromycin, some SSRIs
• PPIs
• Ticagrelor can interact with CYP inhibitors and inducers
• Caution when prescribed with other antiplatelet and anticoagulant agents or NSAIDS- increased bleeding risk

Question 32

name a drug under the class phosphodietserase inhibitors

Answer 32

dipyridamole

Question 33

dipyridamole (Phosphodiesterase inhibitor) uses

Answer 33

• Secondary prevention of ischaemic stroke and TIAs
• Adjunct for prophylaxis of thromboembolism following valve replacement
• Stroke- modified release

Question 34

Mode of action: Dipyridamole

Answer 34

• Inhibits cellular reuptake of adenosine–> increased plasma [adenosine] –> inhibits platelet aggregation via adenosine (A2) receptors
• Also acts as a phosphodiesterase inhibitor which prevents cAMP degradation –> inhibits expression of GP IIb/IIIa
  
  • inhibits activation of platelets

Question 35

Adverse drug response: Phosphodiesterase inhibitors (dipyridamole)

Answer 35

• Vomiting and diarrhoea
• Dizziness

Question 36

Drug-drug interaction: Phosphodiesterase inhibitors (dipyridamole)

Answer 36

• Antiplatelets
• Anticoagulants
• Adenosine

Question 37

name a drug under the class glycoprotein IIb/IIIa inhibitors

Answer 37

abciximab

Question 38

abciximab mode of action

Answer 38

• Blocks binding of fibrinogen and von Willebrand factor (vWF)
  
  • Abciximab= antibody- blocks GPIIb/IIIa receptors >80% reduction in aggregation – bleeding risk
    
    • IV admin
• Target final common pathway- more complete platelet aggregation

Question 39

Adverse drug response: abciximab

Answer 39

Bleeding (dose adjustment for body weight)

Question 40

DDI abciximab

Question 41

name 2 drugs under the class Fibrinolytic agents (thrombolysis) “clot busters”

Answer 41

Alteplase and streptokinase

Question 42

uses of Alteplase and streptokinase

Answer 42

• Acute ischaemic stroke <4.5 hours from symptoms
• Following STEMI diagnosis acutely
• Vs Primary PCL

Question 43

Mode of action of fibrinolytic agens alteplase and streptokinase

Answer 43

activates plasminogen (tissue plasminogen activator) to plasmin which causes fibrinolysis of fibrin clot

Question 44

Adverse drug response: Fibrinolytic agents (thrombolysis)

Answer 44

• Bleeding –> tranexamic acids can be used to stop bleeding

Question 45

Drug-drug interaction: Fibrinolytic agents (thrombolysis)

Answer 45

Other antiplatelet and anticoagulant agents

Question 46

Thrombolysis vs primary PCI following MI

Answer 46

• Offer primary PCI if indicated, as the preferred coronary reperfusion strategy for people with acute STEMI if
  
  • Presentation within 12hours of onset of symptoms and primary PCI can be delivered within 120 mins
    
    • Time critical- ‘time is muscle’
• Insertion of catheter up femoral artery to reach coronary vessel
• Stent and balloon mechanism

If PCI can not be given within 120 mins i.e. in the cath lab… then give fibrinolysis (alteplase/streptokinase)

Question 47

what shoudl be offered to all patients post MI once haemodynamically stable

Answer 47

ACEi