Antiplatelet Agents

Front 1

Differentiate between anti-platelet agents and anticoagulant therapies

Back 1

Anti-platelet therapies are used when thrombi form in the arterial circulation

Anticoagulants are used when there are thrombi in the veins

Front 2

When is thrombus pathological?

Back 2

When normal haemostasis is activated when it should be - rupture/plaques can kickstart clots/thrombi

DVTs can dislodge and go to other sites in the body like the lungs and cause pulmonary embolism, can occlude vessels and limit the supply to tissues

Front 3

What are pathologies associated with thrombosis?

Back 3

Thrombus and embolus

Front 4

What may predispose an individual to thrombosis?

Back 4

• factors in the blood like infection/sepsis, different autoimmune diseases, surgery or malignancy

• damage to vascular endothelium and blood vessels - atherosclerosis within blood vessels as a major risk for the development of MI - damage epithelium and rupture to release pro-thrombolytic material that causes these events to occur

• circulatory status

Front 5

Disorders where there is too little coagulation

Back 5

•genetic like haemophilia

•acquires/induces like liver disease

Front 6

Disorders where there is too much coagulation

Back 6

• venous

• arterial - platelets, white thrombus

Front 7

Targets for thrombosis

Back 7

• platelet function

• blood coagulation

• fibrin removal

Front 8

What influences platelet aggregation?

Back 8

ADP - Aspirin to prevent thrombotic events - MI patients

Front 9

Platelet plug

Back 9

• platelets are anucleated - can’t turnover proteins

• they adhere to the site of injury with adhesion events that involve collagen receptors (VWF) and GPIb-V-IX

• these receptors will signal to the platelet to conformationally change (philpodia) and store mediators like ADP

•thromboxane (arachidonic acid pathway) can be released with the initial signal - aspirin limits its release

• these events lead to the activation of the fibrinogen receptor, which will cross link and bind fibrin - this is latex down by the coagulation cascade - adhesion, activation, stable aggregation

Unhinging of the fibrinogen receptor causes permanent aggregating events, a mutation in this receptor causing Glanzmann thrombasthenia where they cannot form stable thrombi (increased bleeding risk)

Front 10

Name a target drug of the arachidonic acid pathway

Back 10

NSAIDs and aspirin limit the conversion of AA to a lot of lipid mediators such as thromboxane- vasoconstriction in the epithelium and limit bleeding

Aspirin will inhibit the production of thromboxane - prostacyclin is downstream of this pathway under control of COX and COX2 (produced in vascular endothelium) to cause vasodilation

Front 11

What is the active form of aspirin?

Back 11

ASA

Front 12

How does aspirin work to limit thrombi formation? Asp

Back 12

Suppression of prostaglandins (thromboxane) from platelets

Front 13

Aspirin’s MOA

Back 13

• low does for cardiovascular health

• analgesic/anti-inflammatory at higher doses

• gives an acetyl group to inhibit catalytic pockets in enzymes

• inlet irreversible COX1 inhibitor in platelets

• using another NSAID, may reduce aspirin efficacy as they compete for the COX1 enzyme

Front 14

Aspirin as a COX1 inhibitor

Back 14

Low dose will limit thromboxane production. Oral administration. Want to avoid the systemic effects such as anti-inflammatory because platelets are anucleated - if it is inhibited it will be for the rest of its lifetime.

Front 15

What are some long term effects of NSAID use?

Back 15

GI bleeds, peptic ulceration, kidneys needs prostaglandins for normal GFR, pressure and function. Resulting in renal toxicity or aggravate renal disease (mostly high doses)

Rare - Reye’s syndrome

Front 16

ADP receptor (P2Y12)’s role in thrombosis

Back 16

Causes activation which will increase PI3 kinase activation and calcium release when ADP binds, eventually causing platelet aggregation.

Front 17

What is the pro type ADP receptor inhibitor?

Back 17

Clopidegrel - it is a prodrug that needs to be enzymatically converted; oxidated by hepatic CYP2C19 enzyme. Variation in the alleles of this enzyme cause variation in the drug effects- poor metabolizers (decrease enzyme) or rapid metabolizers (enhance activity and convert more, increasing risk of bleeding). Maximum effects occur after 7 days administration (platelets inhibited as cannot act on ADP receptors.

Prasugrel is another ADP receptor inhibitor that is also irreversible, however it is not a prodrug so has greater population efficacy.

Ticagrelor is a reversible form

Front 18

Dipyridamole

Back 18

PDE inhibitor that limits the breakdown of cAMP, thereby reducing calcium and decreasing activation and aggregation. Also inhibits reuptake of adenosine by binding to the adenosine descriptor on platelet

Front 19

Abciximab - fibrinogen receptor irreversible antagonist

Back 19

This is a monoclonal antibody inhibitor of the receptor. It is a potent anti-platelet agent and can increase the risk of bleeding. However, we can develop immunogenicity to the drug and the neutral agent’s effects and therefore it has limited efficacy over time. I

Front 20

Eptifibatide/tirofiban - fibrinogen receptor antagonists e

Back 20

These are synthetic peptides that bind to the receptor

All these agents have the RDG sequence in its structure that is required for it to bind specifically to the fibrinogen receptor.

Fibrinogen is normally in a resting confirmation, activated when platelets are exposed to pro-coagulant factors - platelets are activated and send a signal, calcium will cause a confirmation change

These therapies can bind to the low or high affinity states of the receptor, while fibrinogen only binds the high - this prevents its binding

Front 21

Epoprostenol

Back 21

This is a synthetic prostaglandin analogue, it is chemically unstable as its half life is only 3 minutes. It is administered via IV- it increases AC by stimulate to cause vasodilation and inhibit aggregation. Side effects are flushing, headache and hypotension, only used clinically in specific situations.

Front 22

What is the 1st line anti-platelet agent

Back 22

Aspirin

Clopidogrel in those intolerant/allergic to aspirin

Front 23

Adverse effects of anti-platelet agents

Back 23

• increased bleeding risk, especially fibrinogen receptor inhibitors

•may exacerbate bleeding/peptic ulcerative disease in those with underlying conditions

• avoid in hypertension