4 Antiplatelets, Anticoagulants and Thrombolytics

Question 1

When are antiplatelets used?

Answer 1

Prophylaxis only for arterial thrombosis to prevent platlet aggregation

Anticoagulants is both arterial and venous thrombosis

Question 2

When are anticoagulants used?

Answer 2

For arterial and venous thrombosis
To prevent formation of thrombus

Question 3

Name 4 classes of antiplatelet drugs + examples

Answer 3

1. Non-steroidal anti-inflammatory drugs (NSAIDs):
   Aspirin
2. platelet GP IIb/IIIa receptor blockers:
   Abciximab, Eptifibatide, Tirofiban
3. ADP receptor blockers:
   Ticlopidine, Clopidogrel
4. PDE inhibitor:
   Dipyridamole

Question 4

What is the MoA of Aspirin?

Answer 4

Aspirin is an irreversible COX inhibitor

inhibits the synthesis of Thromboxane A2 from arachidonic acid

Recall Thromboxane A2 promotes platelet aggregation

Overall effect: prevents platelet aggregation

see diagram on pg 6 (& pg 23 in nsaids)

Question 5

efficacy of aspirin

Answer 5

inhibitory effect is rapid and lasts the lifespan of the platelet (~7-10 days)

Question 6

Name 3 clinical uses for aspirin

Answer 6

1. Prophylactic treatment of transient cerebral ischemia
2. Reduce the incidence of recurrent myocardial infarction
3. Decrease mortality in postmyocardial infarction patients

Question 7

Name 2 adverse effects of aspirin

Answer 7

Bleeding (Prostacyclin, PGI2)
Gastric upset and ulcers (Prostaglandin, PGE2)
*GI bleeding

Recall Prostaglandin protects walls of stomach

Question 8

Name 3 platelet GP IIb/IIIa receptor blockers

Answer 8

Abciximab
Eptifibatide
Tirofiban

Question 9

2 clinical uses for platelet GP IIb/IIIa receptor blockers

Answer 9

1. Prevent restenosis after coronary angioplasty
   combination therapy: aspirin + heparin + abciximab
2. Used in acute coronary syndromes

Acute coronary syndrome is a term used to describe a range of conditions associated with sudden, reduced blood flow to the heart. One such condition is a heart attack (myocardial infarction) — when cell death results in damaged or destroyed heart tissue.

Question 10

MoA of abciximab

Answer 10

a humanized monoclonal Ab directed against the IIb/IIIa complex

reversibly inhibits the binding of fibrinogen and other ligands to GP IIb/IIIa

Question 11

MoA of eptifibatide

Answer 11

an analog of the sequence at the extreme carboxyl terminal of the delta chain of fibrinogen, which mediates the binding of fibrinogen to the receptor

pretends to be fibrinogen
acts as competitive inhibitor

Question 12

MoA of tirofiban

Answer 12

a small molecule blocker of the GP IIb/IIIa receptor

Question 13

Name 2 ADP receptor blockers

Answer 13

Clopidogrel
Ticlopidine

Question 14

MoA of clopidogrel and ticlopidine

Answer 14

blocks ADP receptors on platelets
→ inhibits ADP induced platelet aggregation

class: ADP receptor blockers

Question 15

Name a PDE inhibitor

PDE: phosphodiesterase

Answer 15

Dipyridamole

Question 16

MoA of dipyridamole

Answer 16

inhibits PDE
→ prevents conversion of cAMP to 5’-AMP
→ high cAMP inhibits release of platelet granules )(containing serotonin and ADP)

Recall PDE converts cAMP to 5’ AMP

class: PDE inhibitor

Question 17

Name 3 anticoagulants

Answer 17

• antithrombin III (ATIII)
• heparin
• warfarin

Question 18

MoA of Antithrombin III

Answer 18

irreversibly inactivates thrombin (IIa), IXa, Xa by forming stable complexes with them

2a, 9a, 10a

Question 19

MoA of Heparin

Answer 19

binds to AT III and cause a conformational change, which exposes the active site of AT III for more rapid interaction with the proteases (IIa, IXa, Xa)

To inhibit thrombin (IIa), heparin must bind to AT III and thrombin (IIa)

To inhibit factor Xa, heparin only need to bind to AT III

LMWH has longer duration of action than heparin but doesn’t work on thrombin (IIa)

Question 20

Name 3 clinical uses for heparin

Answer 20

1. treatment of DVT, pulmonary embolism (PE), AMI
2. use in combination with thrombolytics for revascularization
   Thrombolytics: t-PA, urokinase, streptokinase, anistreplase

use in combination with GP IIb/IIIa inhibitors during angioplasty and placement of coronary stents
GP IIb/IIIa inhibitors: Abciximab, Eptifibatide, Tirofiban

3. preferred anticoagulant to use in pregnancy

Question 21

What is the route of administration for Heparin?

Answer 21

IV or SC

Never give IM → will result in haematomas!

Question 22

Name 2 adverse effects of Heparin

Answer 22

1. Haemorrhage
   stop heparin therapy + give protamine sulfate
2. Thrombosis and thrombocytopenia (platelet count too low)

When do you give protamine sulfate for heparin?
Before surgery
After renal dialysis, open heart surgery
If excessive bleeding occurs
When overdose on heparin

Question 23

Vitamin K is ___ soluble.
Vitamin K is essential for the formation of clotting factors ___.

Answer 23

fat
II, VII, IX and X

Reduced vitamin K is an essential cofactor in the carboxylation of glutamate residues found in factors 2, 7, 9, 10

Question 24

Name 2 clinical uses for Vitamin K

Answer 24

1. Treatment and/or prevention of bleeding
   - resulting from use of oral anticoagulant drugs e.g. warfarin
   - babies: to prevent haemorrhagic disease of the newborn
2. For vitamin K deficiencies in adults

Note that vitamin K takes time to reverse the effects of anticoagulants. If urgent, use fresh frozen plasma

Question 25

MoA of Warfarin

Answer 25

Inhibits vitamin K reductase → depletes active vitamin K → inhibits synthesis of clotting factors II, VII, IX and X

Question 26

Name 2 clinical uses for Warfarin

Answer 26

Same as heparin: 1. treatment of DVT, pulmonary embolism (PE), AMI 2. use in combination with thrombolytics for revascularization *Thrombolytics: t-PA, urokinase, streptokinase, anistreplase* use in combination with GP IIb/IIIa inhibitors during angioplasty and placement of coronary stents *GP IIb/IIIa inhibitors: Abciximab, Eptifibatide, Tirofiban* but **CANNOT USE IN PREGNANCY**

Question 27

Pharmacokinetics of Warfarin a. Route of administration b. Elimination

Answer 27

a. Route of administration: Oral Rapid absorption Small Vd because strongly bound to plasma albumin b. Elimination depends on metabolism by hepatic cytochrome P450 ## Footnote Lipid-soluble so strongly bound to plasma albumin Albumin has hydrophobic binding domains in which drugs such as warfarin and diazepam can bind.

Question 28

Name 2 adverse effects of Warfarin

Answer 28

1. Haemorrhage (bleeding) 2. Warfarin should NEVER be administered during pregnancy. - Warfarin crosses the placenta readily and can cause a hemorrhagic disorder in the fetus. - Fetal proteins with gamma-carboxyglutamate residues found in bone and blood may be affected by warfarin | if pregnant woman need anticoagulant, use heparin

Question 29

Warfarin - DDI Think Cytochrome P450 (Warfarin is metabolised by CYP450)

Answer 29

CYP P450 inducers - Barbiturates - Carbamazepine - Phenytoin CYP P450 inhibitors (bad, accumulate Warfarin) - Amiodarone (antiarrhythmic) - Cimetidine - Disulfiram - Imipramine (antidepressant - TCAs)

Question 30

Name 4 Thrombolytic agents

Answer 30

1. t-PA (alteplase) 2. urokinase 3. streptokinase 4. anistreplase t-PA: tissue plasminogen activator

Question 31

MoA of thrombolytics

Answer 31

activates conversion of plasminogen to plasmin → plasmin breaks down fibrin into fibrin degradation products | final effect: lysis of current clot

Question 32

Name 3 clinical uses for thrombolytics

Answer 32

1. EMERGENCY treatment of coronary artery thrombosis 2. Peripheral arterial thrombosis and emboli 3. Ischaemic stroke (< 4.5 h window)

Question 33

Route of administration of thrombolytics

Answer 33

Intracoronary injection, IV injection | not oral bruh, it's for emergency!

Question 34

State 1 adverse effect and 2 contraindications of thrombolytics

Answer 34

Adverse effect: Haemorrhage (Bleeding) Contraindication: Healing wound, Pregnancy