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Clinical Pharmacology > 6.2 antiplatelets > Flashcards

6.2 antiplatelets Flashcards

1
Q

give some examples of thromboembolic diseases

A 
deep vein thrombosis (DVT) 
pulmonary embolism (PE)
consequence of atrial fibrillation (AF)
transient ischaemic attacks (TIA) and ischaemic stroke
myocardial infarction (MI)
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2
Q

what is a thrombus?

A

a clot that is adhered top the vessel wall

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3
Q

what is an embolus?

A

a clot or other plug, usually part or all of a thrombus, brought by the blood from another vessel and forced into a smaller one, thus obstructing circulation

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4
Q

what component of virchows triad is usually affected to cause venous thombosis?

A

blood flow - associated with stasis of blood or damage to the veins obstructing flow, less likely to see endothelial damage

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5
Q

describe the composition of a venous thrombus?

A 
high red cell count and fibrin content 
deep red
low platelet content that is evenly distributed 
soft
gelatinous
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6
Q

where do arterial thombosis usually form?

A

Usually form at the site of atherosclerosis following plaque rupture

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7
Q

describe the structure of a arterial thrombus

A 
pale
lower fibrin and cell count
higher platelet count 
granular
lines of Zahn
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8
Q

how does healthy endothelium prevent thrombus formation?

A
  1. produces and releases prostacyclins (PGI2)
  2. prostacyclins bind to platelet receptors and increase cAMP in platelets
  3. This low energy signal decreases the release of sequestered calcium
  4. low calcium prevents platelet aggregation
  5. there is a decrease in platelet aggregatory agents. and the inactive GPII/IIIa receptors are stabilised
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9
Q

what is the average platelet lifespan?

A

8 to 10 days

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10
Q

describe the process of platelet activation in the formation of an arterial thrombus?

A

blood comes into contact with sub endothelial factors such as collagen and vWf. activated platelets cover and adhere to exposed subendothelial surface of the damaged endothelium. These platelets release chemical mediators such as thromboxane A2, ADP, serotonin and PAF. This extensive cascade of signalling molecules activates and recruits more platelets.

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11
Q

describe the process of platelet aggregation in the formation of arterial thrombus

A

signalling molecules such as thromboxane A2, ADP, serotonin and PAF cause an increase in platelet calcium levels. This causes activation of the GPIIb/IIIa receptors and aggregation through these and fibrinogen. The signalling molecules continue to be releases and cascade and amplification occurs from platelet to platelet.

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12
Q

how does the shape of platelets change during their activation?

A

change from being a domed shape to elliptical.

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13
Q

what drug classes are used to treat platelet rich white arterial thrombi?

A

antiplatelet and fibrinolytic drugs

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14
Q

what drug classes are used in the treatment of red venous thrombus?

A 
parental anticoagulants (heparins)
oral anticoagulants (warfarin)
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15
Q

what is the drug class of aspirin?

A

cyclo-oxygenase inhibitor

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16
Q

what is the mechanism of action of aspirin?

A

Aspirin inhibits COX-1 mediated production of TXA2 and reduces platelet aggregation irreversibly. Potent platelet aggregating agent thromboxane A2 (TXA2) is formed from arachidonic acid by COX-1

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17
Q

why does aspirin not completely inhibit platelet aggregation?

A

as activated platelets release other chemical mediators such as ADP, serotonin and PAF that are not inhibited via aspirin.

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18
Q

how does the dose of aspirin affect its therapeutic use?

A

at low doses (75mg) aspirin has an antiplatelet effect

at higher doses ( 300mg) aspiring has an analgesic effect

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19
Q

how does aspirin work as an analgesic?

A

works at higher doses to inhibit the endothelial prostacyclin (PGI2)

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20
Q

what are the ADRs of aspirin?

A

Gastrointestinal irritation, GI bleeding (peptic ulcer), haemorrhage (stroke)
hypersensitivity

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21
Q

what are the contraindications of aspirin?

A

Reye’s syndrome – avoid <16 years
Hypersensitivity
3rd trimester – premature closure of ductus arteriosus

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22
Q

what is Reye’s syndrome?

A

a rare disorder occurring primarily in children after a viral illness and associated with aspirin usage, characterized by vomiting, swelling of the brain, and liver dysfunction.

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23
Q

what are the important drug interactions fo aspirin?

A

caution - other antiplatelet and anticoagulants (additive/synergistic action)

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24
Q

why is aspirin not equally effective in all people?

A

Due to COX-1 polymorphisms result in lack of efficacy in some people

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25
Q

Why does the antiplatelet effect of aspirin last lifespan of platelet (7-10 days)?

A

as aspirin binds irreversibly to COX-1 to prevent it forming thromboxane A2

26
Q

what are the indications of aspirin?

A

AF (before anticoagulants)
Secondary prevention of stroke and TIA
Secondary prevention of acute coronary syndromes (ACS)
Post primary percutaneous coronary intervention (PCI) and stent to reduce ischaemic
complications
Often co prescribed with other antiplatelet agents
NSTEMI/STEMI - initial once only 300 mg loading dose – chewable is best!
acute ischaemic stroke initial 300 mg daily 2 weeks

27
Q

what is often co-prescribed with long term aspirin?

A

PPI - Gastric protection required for long term use in at risk patients

28
Q

give examples of ADP receptor antagonists

A

clopidogrel
prasugrel
ticagrelor

29
Q

describe the mechanism of action of clopidogrel

A

inhibits the binding of ADP to the P2Y12 receptor. This inhibits the activation of the GPIIb/IIIa receptors. Independent of COX pathway. Binds irreversibly with a slow onset of action without a loading dose. (ticagrelor and prasugrel have a more rapid inset of action)

30
Q

why does omeprazole stop clopidogrel and prasugrel from working?

A

As omeprazole is a CYP2C19 inhibitor it reduces the hepatic metabolism of clopidogrel and prasugrel. As they are prodrugs, it is their metabolites that are active and therefore if there are less metabolites produced, they have less function.

31
Q

what is the major difference in function of clopidogrel and ticagrelor?

A

but are prodrugs that act as antiplatelets. clopidogrel binds irreversibly to inhibit the binding of ADP to P2Y12. Ticagrelor binds reversibly to a different site

32
Q

what are the ADRs of ADP receptor antagonists

A

Bleeding! GI upset – dyspepsia and diarrhoea

rarely - thrombocytopenia

33
Q

when are ADP receptor antagonists contraindicated?

A

caution in high bleed risk patients with renal and hepatic impairment

34
Q

what are the important drug interactions of ADP receptor antagonists?

A

CYP inhibitors – omeprazole, ciprofloxacin, erythromycin, some SSRIs
Need to consider use of other PPIs with clopidogrel
ticagrelor can interact with CYP inhibitors and inducers
caution when co prescribed with other antiplatelet and anticoagulant agents or NSAIDs – increased bleeding risk

35
Q

why does clopidogrel need stopping 7 days before surgery

A

As it binds irreversible to stop ADP binding at the P2Y12 receptor. The lifespan of a platelet is 7 to 10 days, therefore this allows time for new platelets that do not have clopidogrel bound to enter circulation

36
Q

what are the indications of ADP receptor antagonists?

A

Clopidogrel
- mono therapy where aspirin is contraindicated
NSTEMI patients – 3 months
STEMI patients - up to 4 weeks
Ischaemic stroke and TIA long term secondary prevention
Prasugrel and ticagrelor with aspirin in ACS patients (undergoing PCI) for up to 12 months

37
Q

why is ticagrelor with aspirin prescribed in ACS patients instead of clopidogrel and aspirin?

A

As ticagrelor has a faster onset of action

38
Q

give an example of a phosphodiesterase inhibitor

A

dipyridamole

39
Q

what is the mechanism of action of dipyridamole?

A

dipyridamole inhibits cellular reuptake of adenosine → increased [adenosine] → inhibits platelet aggregation via adenosine (A2) receptors
Also acts as phosphodiesterase inhibitor which prevents cAMP degradation → inhibit expression of GPIIb/IIIa

40
Q

what are the adverse drug reactions of dipyridamol

A

vomiting and diarrhoea

dizziness

41
Q

what are the drug interactions of dipyridamol?

A

antiplatelets
anticoagulants
adenosine

42
Q

what is the indication of dipyrimadol?

A

antiplatelet
secondary prevention of ischaemic stroke and TIAs
Adjunct for prophylaxis of
thromboembolism following valve replacement
Stroke – modified release

43
Q

what drug class is abciximab?

A

monoclonal antibody - glycoprotein IIb/IIIa inhibitors

44
Q

what is the mechanism of action of abciximab?

A

Abciximab is a monoclonal antibody that blocks GPIIb/IIIa receptors. This blocks binding of fibrinogen and von Willebrand factor (vWF). Target final common pathway – more complete platelet aggregation (>80% reduction in aggregation)§

45
Q

what are the ADRs for abciximab?

A

bleeding risk - dose adjusted for body weight and given IV

46
Q

what are the indications for abciximab?

A

antiplatelet - Specialist use in high risk percutaneous transluminal coronary angioplasty patients with other drugs

47
Q

what drug class is alteplase?

A

a fibrinolytic agent

48
Q

what is the function of alteplase?

A

to dissolve the fibrin meshwork of thrombus.

49
Q

what are the indications of alteplase?

A

Alteplase in acute ischaemic stroke <4.5 hours from symptoms. Clot buster

50
Q

what is the mechanism of action of streptokinase?

A

a fibrinolytic agent used to dissolve the fibrin meshwork of thrombus

51
Q

why is alteplase used instead of streptokinase in STEMIs ?

A

As streptokinase is similar, both in function and in structure, to staphylokinase found in Staphylococcus aureus. Staphylokinase is considered a virulence factor and after infection by a haemolytic staphylococcus we develop antibodies to these enzymes. Therefore streptokinase can only be used once

52
Q

when is primary PCI offered preferentially to treat an acute STEMI?

A

offered if:
presentation is within 12 hours of onset of symptoms and primary PCI can be delivered within 120 minutes of the time when fibrinolysis could have been given.

53
Q

ACEi should be offered to all patients post MI once haemodynamically stable. Why?

A

as reduces the circulating volume of extracellular fluid, decreases the pressure on the heart and therefore the amount of CV remodelling

54
Q

Why are antiplatelet drugs used in secondary prevention of ACS and TIA?

A

ACS occurs when there is acute narrowing of one of the major arteries supplying the heart. TIAs occurs when there is narrowing of one of the arteries supplying the brain. As arterial thrombi have a high platelet content and a low cell content, antiplatelet drugs such as aspirin and ticagrelor are more effective.

55
Q

Why does it take ~ 7-10 days for antiplatelet effects to cease after terminating aspirin treatment?

A

As aspirin irreversibly inhibits the COX-1 mediated production of TXA2 and reduces platelet aggregation. As the average lifespan of a platelet is 7 to 10 days, it takes this long for the platelets to be cleared and replaced by fresh platelets not affected by aspirin.

56
Q

Why is clopidogrel contraindicated in hepatic failure?

A

As it is a prodrug that requires hepatic CYP enzymes to act upon it to produce its active metabolites. Higher doses of the drug would be around for longer as it cannot be metabolised

57
Q

How do clopidogrel and ticagrelor differ in their basic pharmacodynamic properties

A 
clopidogrel = slow onset of action. binds irreversibly to inhibit platelet aggregation 
ticagrelor = fast onset of action. binds reversibly to inhibit platelet aggregation
58
Q

Why do GP IIb/IIIa inhibitors afford more complete platelet aggregation than other agents?

A

As it blocks the final common pathway. Other agents target a step before this in the pathway and therefore other pathways can still produce platelet aggregation.

59
Q

What is tranexamic acid used for?

A

tranexamic acid stops fibrinolysis and therefore promotes clotting of blood and stops bleeding. Used in severe epitaxis and post partum bleeding

60
Q

What are the downstream consequences of dipyridamole’s phosphodiesterase inhibiting action?

A

as one of mechanisms of action of dipyridamol is to inhibit cellular reuptake of adenosine, it increases the plasma concentration of adenosine.
Adenosine is a natural nucleoside that binds to A1 receptors in the heart to block adenylyl cyclase and thus reduces intracellular cAMP. This causes hyperpolarisation as there is a decrease in calcium currents. AV node conduction is slowed and there is an increased refractory period. It should not be used alongside adenosine, an antiarrhythmic agent.

Clinical Pharmacology (26 decks)

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