1. Antiplatelet Drugs Dr. : Asmaa Fady MD., MSC, M.B, B.Ch
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5/14/2019

2. Learning Objectives:
To describe different classes of anti-platelet drugs and their mechanism of action
To explain the pharmacological effects, pharmacokinetics, clinical uses and adverse effects of anti-platelet drugs.
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5/14/2019

3. Normal body antithrombotic mechanism
PGI2 receptors
PGI2 (prostacyclin)
N.O
+++ GC
+++ AC
GTP cGMP
ATP cAMP
Ca+
Decreased calcium level leads to Inhibition of platelet aggregation
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5/14/2019

4. mechanism of normal hemostasis
Hemostasis is the spontaneous arrest of bleeding from a damaged blood vessel.
Tissue (BV) injury.
1- V.C
2- Exposure of sub-endothelial Collagen and VW factor.
3-interaction with receptors in the surface of the platelets: activation to the platelets.
4- adhesion to damaged space.
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5/14/2019

5. mechanism of normal hemostasis
activated platelets release the following substances:
phospholipids arachidonic acid (releasing Thromboxane A2) TX A2: vasoconstriction and platelet recruitment.
ADP (act on ADP receptors on other platelets): cAMP & Ca+
PAF (platelet activating factors).
Thrombin.
Serotonin (just stored not synthetized inside platelets): V.C & increase platelet aggregation.
COX1
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6. mechanism of normal hemostasis
5- Platelet aggregation.
6- platelet plug formation.
7- Fibrin clot formation.
8- Clotting factors cascade to stabilize fibrin clot.
9-The presence of fibrin triggers the activation of plasminogen to plasmin, through tissue plasminogen activator (t-PA).
10- Plasmin then splits fibrin and fibrinogen into fragments leading to clot dissolution.
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5/14/2019

7. Mechanism of platelet plug reinforcement by fibrin threads formation
Glycoprotein IIb /III/a receptors (GPIIb/IIIa): normally inactive
Delta chain of fibrinogen
CA++
ADP receptors
ADP
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8. Hemostatic mechanism which produce Xa Intrinsic pathway
Extrinsic pathway
Soluble fibrinogen
Insoluble fibrin
Prothmbin (II) thrombin (IIa)
plasminogen
plasmin
Tissue plasminogen activator
Lysis of fibrin clot
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5/14/2019

9. Drugs affecting blood hemostasis
- - -
Anticoagulants
- Coagulation factors
Anti-platelets
- Platelet plug formation
Thrombolytics
Dissolve already formed clot
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5/14/2019

10. Factors affecting platelet plug formation
TXA2
PGI2
ADP NO
GPIIb/IIIa
cAMP- cGMP
So, antiplatelet drugs are :
Anti COX1 (aspirin).
ADP receptor blockers.
GPIIb/IIIa receptor blocker
cAMP- cGMP (increase production: or inhibit breakdown by phosphodiesters enzyme)
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5/14/2019

11. Thrombus is formed mainly from: Platelets + fibrin
Platelets mainly
Arteries.
Ppt. by: Smoking, DM, HTN.
Ttt: by anti-platelets & thrombolytics
White thrombus
Mainly fibrins.
Venous
Ppt. by stasis of blood, DVT.
Ttt by anticoagulants
Red thrombus
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12. Antiplatelet Agents Antiplatelet drugs aspirin
Inhibition of prostaglandin TXA2 synthesis (COX1 I)
aspirin
Inhibition of ADP-induced platelet aggregation
*clopidogrel, *ticlopidine
Blockade of glycoprotein IIb/IIIa receptors on platelets
*abciximab *tirofiban *eptifibatide
additional antiplatelet drugs
*Dipyridamole *cilostazol
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5/14/2019

13. 1- PG synthesis inhibitors: small dose Aspirin
Mechanism of action:
Aspirin produces irreversible (inhibition) of the enzyme cyclo- oxygenase (COX-1) in platelets leading to:
Inhibits synthesis of thromboxane A2 (TXA2) which is necessary for clumping of platelets.
Suppression of platelet aggregation last for the life of the platelet, which is approximately 7 to 10 days.
This shifts the balance to increase PGI2 (Prostacyclin) formation with decrease in platelet aggregation.
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5/14/2019

14. 1- PG synthesis inhibitors: small dose Aspirin
Therapeutic Uses:
Prophylaxis of thromboembolism e.g. prevention of ischemic stroke and myocardial infarction.
Prevention of ischemic events (myocardial infarctions) in patients with unstable angina pectoris.
can be combined with other antiplatelet drugs (clopidogrel) or anticoagulants (heparin).
Side effects:
Risk of peptic ulcer.
Increased incidence of GIT bleeding (aspirin prolongs bleeding time).
Ppt. asthma in asthmatic patients.
Dose:
Low-dose aspirin ‘’baby aspirin’’ ( mg) is the most common dose used to prevent a heart attack or a stroke.
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15. 2- ADP- receptor antagonists
Pharmacodynamics (Mechanism of action):
They inhibit (irreversibly) the binding of ADP to its receptors on platelets and, thereby, inhibit the activation of the GP IIb/IIIa receptors required for platelets to bind to fibrinogen and to each other.
Pharmacokinetics:
Administered orally.
Maximum effect is achieved after 3-5 days.
Activated by CYP450.
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16. 2- ADP- receptor antagonists: Clopidogrel (Plavix)
Is a prodrug activated in the liver by cytochrome P450 enzymes.
So, interactions with drugs that inactivate liver microsomal enzymes e.g. (Proton Pump Inhibitors, i.e omperazole).
اسم ورقم المقرر – Course Name and No.
5/14/2019

17. 2- ADP- receptor antagonists:
Therapeutic uses:
unstable angina.
acute myocardial infarction.
CNS stroke and stent insertion.
New ADP Pathway Inhibitors :
ticlopidine
Side Effects:
Clopidogrel has fewer side effects.
ticlopidine causes bone marrow suppression (neutropenia)
5/14/2019

18. 3- Glycoprotein IIb/ IIIa receptor antagonists
Abciximab, Tirofiban & Eptifibatide
They block platelet GP IIb/IIIa receptors (activation of this receptor complex is the "final common pathway" for platelet aggregation)
Abciximab consists of monoclonal antibodies which bind to receptors.
Eptifibatide, and tirofiban are analogs to delta chain of fibrinogen which mediates binding of fibrinogen to GP IIb/IIIa receptors on platelets.
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5/14/2019

19. 3- Glycoprotein IIb/ IIIa receptor antagonists
Given only by IV
They are given intravenously with aspirin and heparin for the reduction of incidence of thrombotic complications during coronary angioplasty.
Major side effects is bleeding.
No specific antidote.
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5/14/2019

20. 4- Phosphodiesterase inhibitors: Dipyridamole
Mechanism of action:
Dipyridamole is a coronary vasodilator.
It increases intracellular levels of cAMP, cGMP by inhibiting cyclic nucleotide phosphodiesterase.
It decreased thromboxane A2 synthesis.
Therapeutic uses:
in combination with aspirin to prevent cerebrovascular ischemia.
in combination with warfarin for primary prophylaxis of thromboembolism in patients with prosthetic heart valves.
Adverse effects: cAMP in heart & blood vessels ( ca+ cardiac work, worsen angina)
Dizziness and hypotension
Headache and gastrointestinal disturbances.
unlike aspirin, it does not increase
the risk of bleeding.
Weak Cannot be used alone.
High dose leads to adverse effects
Obsolete drug due to its side effects
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5/14/2019

21. 4- Phosphodiesterase inhibitors: Cilostazol
It is an oral antiplatelet agent that also has vasodilating activity.
Selective inhibit phosphodiesterase 3 enzyme cAMP so inhibit platelet aggregation.
It is used primarily for treatment of intermittent claudication.
Cilostazol is contraindicated in patients with heart failure.
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5/14/2019

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