Lecture 12- Anti-platelet and fibrinolytic drugs Flashcards
1
Q
Thrombus
A
- a clot adhered to vessel wall
2
Q
Embolus
A
- intravascular clot distal to site of origin
3
Q
Thromboembolic diseases are common
A
· deep vein thrombosis (DVT) and pulmonary embolism (PE)
· consequence of atrial fibrillation (AF)
· transient ischaemic attacks (TIA)
· ischaemic stroke
· myocardial infarction (MI
4
Q
arterial thrombosis
A
- Usually forms at site of atherosclerosis following plaque rupture
- Lower fibrin content and much higher platelet content than venous thrombosis
5
Q
Venous thrombosis
A
- 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
6
Q
healthy endothelium
A
‘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
7
Q
what inhibits platelt aggregation
A
prostacylin (PGI2) produced by healthy endothelium
8
Q
Platelet lifespan
A
8-10 days
- 10% replaced each day turnover
9
Q
Platelet activation and aggregation
A
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
10
Q
Reduction of pathological platelet aggregation essential in
A
reducing cardiovascular events and reducing mortality
11
Q
Therapeutic agents available disrupt various stages of signalling cascade
A
- 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
12
Q
A
13
Q
name the antiplatelet classes
A
- Cyclo-oxygenase inhibitors
- ADP receptor antagonists
- Phosphodiesterase inhibitors
- glycoprotein IIb/IIIa inhibitors
14
Q
clot busters
A
fibrinolytic agents - mediate thrombolysis
15
Q
name a drug under the class cyclo-oxygenase inhibitor
A
aspirin
16
Q
uses of aspirin (cyclo-oxygenase inhibitor)
A
- 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
17
Q
Pharmacokinetics Aspirin (Cyclo-oxygenase inhibitor)
A
- Absorbed by passive diffusion
- Hepatic hydrolysis to salicylic acid (active form)
- COX-1 polymorphism results in lack of efficacy in some
18
Q
mode of action of aspirin
A
- 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
19
Q
low dose aspirin
A
Daily low-dose aspirin is a blood thinning medicine- 75mg
20
Q
Adverse drug response: aspirin
A
- GI irritation (gastric protection required for long term use in at risk pts (PPIs needed)
- GI bleeding (peptic ulcer)
- Haemorrhage (stroke)
- Hypersensitivity to aspirin
21
Q
Contraindications: aspirin
A
- Reyes syndrome – avoid <16 years
- Causes liver disease and brain damage
- Hypersensitivity to aspirin
- 3rd trimester- premature closure of ductus arteriosus
22
Q
Drug-drug interaction: aspirin
A
Caution- other antiplatelets and anticoagulants (additive/ synergistic action)
23
Q
name 3 drugs under the class ADP receptor antagonist
A
-
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)
24
Q
when are ADP receptor antagonists used e.g. clopidogrel
A
- MI
- ischaemic stroke
25
**Mode of action**
* ADP receptor antagonist- inhibits binding of ADP to P2Y12 receptor
* Inhibiting activation of GPIIb/IIIa receptors (independent of COX pathway)
26
clopidogrel pharmacokinetics
* 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
27
prasugrel pharmacokinetics
* Irreversible inhibitors of P2Y12
* Prodrugs- need hepatic metabolism to produce active metabolites
* rapid onset
28
Ticagrelor pharmacokinetics
Acts reversibly at different sites to clopidogrel and has active metabolites
29
**Adverse drug response: ADP receptro antagonists e.g. clopidogrel**
* Bleeding
* GI upset- dyspepsia and diarrhoea
* thrombocytopenia
30
**Contraindications** ADP receptor antagonists e.g. clopidogrel
* caution in high bleed risk pts with renal and hepatic impairment
* **clopidogrel needs stopping 7 days prior to surgery**
31
**Drug-drug interaction:** ADP receptor antagonist e.g. clopidogrel
* 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
32
name a drug under the class phosphodietserase inhibitors
dipyridamole
33
dipyridamole (Phosphodiesterase inhibitor) uses
* Secondary prevention of ischaemic stroke and TIAs
* Adjunct for prophylaxis of thromboembolism following valve replacement
* Stroke- modified release
34
**Mode of action:** Dipyridamole
* 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
35
**Adverse drug response:** Phosphodiesterase inhibitors (dipyridamole)
* Vomiting and diarrhoea
* Dizziness
36
Drug-drug interaction: Phosphodiesterase inhibitors (dipyridamole)
* Antiplatelets
* Anticoagulants
* Adenosine
37
name a drug under the class glycoprotein IIb/IIIa inhibitors
abciximab
38
abciximab mode of action
* 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
39
**Adverse drug response: abciximab**
Bleeding (dose adjustment for body weight)
40
DDI abciximab
41
name 2 drugs under the class Fibrinolytic agents (thrombolysis) “clot busters”
Alteplase and streptokinase
42
uses of Alteplase and streptokinase
* Acute ischaemic stroke \<4.5 hours from symptoms
* Following STEMI diagnosis acutely
* Vs Primary PCL
43
**Mode of action of fibrinolytic agens alteplase and streptokinase**
**activates plasminogen (tissue plasminogen activator) to plasmin which causes fibrinolysis of fibrin clot**
44
**Adverse drug response:** Fibrinolytic agents (thrombolysis)
* Bleeding --\> tranexamic acids can be used to stop bleeding
45
**Drug-drug interaction:** Fibrinolytic agents (thrombolysis)
Other antiplatelet and anticoagulant agents
46
**Thrombolysis vs primary PCI following MI**
* 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)**
47
what shoudl be offered to all patients post MI once haemodynamically stable
ACEi
