Anti-Platelet Drugs

• Anti-platelet drugs prevent and inhibit platelet activation and aggregation
• They are used as prophylactic therapy in high-risk patients.
• It is highly recommended to study platelet physiology before this lecture

Objectives

• Basic concepts of platelet activation and aggregation
• Knowledge of anti-platelet drugs
  • Inhibition of thromboxane A2 synthesis via inhibiting COX-1: Aspirin
  • Antagonist of ADP receptors: Clopidogrel, Ticlopidine
  • GP IIb/IIIa receptor antagonists: Abciximab, Tirofiban, and Eptifibatide
  • Phosphodiesterase 3 (PDE) inhibitors/adenosine uptake inhibitors
• Understanding the pharmacotherapeutic profile of individual classes, including their mechanisms, indications, and adverse drug reactions

Platelets and Clots

• Circulating platelets are maintained in an inactive state by nitric oxide (NO) and prostacyclin (PGI2), which are released by endothelial cells lining the blood vessels.
• Injury to the vessel wall results in the interaction between platelets, the endothelial system, and coagulation factors, leading to clot formation.

Platelet Activation After Vascular Injury

• Injury exposes reactive subendothelial matrix proteins and causes platelet adherence and activation, as well as secretion and synthesis of vasoconstrictors and platelet-activating molecules.
• Thromboxane A2 (TXA2) is synthesized from arachidonic acid within platelets, acting as a platelet activator and potent vasoconstrictor
• Adenosine diphosphate (ADP) is secreted from platelets and is a powerful inducer of platelet aggregation
• Serotonin (5HT) induces aggregation and vasoconstriction
• Platelet Activation leads to aggregation and conformational change in the GPIIb/IIIa
  • This enables fibrinogen to bind, cross-linking adjacent platelets and forming a platelet plug
• The coagulation system cascade is activated simultaneously, resulting in thrombin generation and a fibrin clot that stabilizes the platelet plug.

Clot types

• Thrombus - A clot that adheres to a vessel wall
• Embolus - A clot that floats in the blood
• Thrombosis - The formation of an unwanted clot within blood vessels, which can lead to life-threatening conditions
  • Acute myocardial infarction (MI)
  • Acute ischemic stroke (AIS)
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)

Drugs Used In Thrombosis

• Anticoagulants - prevent clotting by inhibiting clotting factors (coagulation process)
  • Used in the prevention and treatment of thrombosis
• Thrombolytics or Fibrinolytics - reduce or lyse clots
  • Used in the acute treatment of thrombosis.

Drugs Target For Platelet Inhibition

• Inhibition of thromboxane A2 synthesis via inhibiting COX-1
  • Aspirin
  • Oral administration
• Inhibition of ADP-induced platelet aggregation (ADP receptor antagonists)
  • Clopidogrel, Ticlopidine
  • Oral administration
• GP IIb/IIIa receptor antagonists (Inhibitors)
  • Abciximab, Tirofiban, Eptifibatide
  • IV administration
• Phosphodiesterase 3 (PDE) inhibitor/adenosine uptake inhibitors
  • Dipyridamole, Cilostazol
  • Oral administration

Arachidonic Acid Pathway Inhibitors

• Aspirin (Acetylsalicylic Acid)
  • Irreversibly inhibits cyclooxygenase enzyme (COX-1) via acetylation
  • Inhibits the synthesis of TXA2
  • Low doses (75-160 mg) selectively inhibit COX-1
  • Decreases synthesis of platelet thromboxane (TXA2), inhibits platelet aggregation, but spares the protective PGI2 synthesis
  • Used for prophylaxis of thromboembolism e.g. unstable angina, myocardial infarction, and ischemic stroke
  • Can be combined with other antiplatelet aggregating agents like clopidogrel and anticoagulants like heparin ADRs
  • Hyperacidity (Risk of peptic ulcer)
  • Allergy
  • Increased incidence of GIT bleeding (aspirin prolongs bleeding time)
  • Do not take if peptic ulcer is present

ADP Pathway Inhibitors

• Ticlopidine
  • More toxic
• Clopidogrel
  • Irreversibly blocks the ADP receptor of platelets
  • Inhibits ADP-induced expression of platelet membrane GPIIb/IIIa and fibrinogen binding to activated platelets
  • Pro-drugs requirement
    • They require metabolism by the hepatic cytochrome p450 (CYP) enzyme system to become active
  • Prevents thrombosis (unlike aspirin, which is used as a primary prophylactic)
  • Prevents vascular events in patients with transient ischemic attacks, unstable angina pectoris, and those with a coronary stent Specific indications;
  • Patients with a history of a recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, and patients with acute coronary syndrome
  • Can be used either when managed medically or with percutaneous coronary intervention (PCI) with or without a stent ADRs
• GIT: nausea, dyspepsia, diarrhea.
• Hemorrhage (prolongs bleeding time)
• Leukopenia
• TTP (thrombotic thrombocytopenic purpura) Precaution
• Regular monitoring of WBC count during first three months
• Regular monitoring for neutropenia
• Clopidogrel has replaced ticlopidine
  • more potent
  • has a better safety profile

Antiplatelet Drugs

• Prevent blood clots from forming in the arteries
• Monitoring of bleeding time as antiplatelet drugs increase bleeding time
• Aspirin is the most commonly prescribed antiplatelet drug

Aspirin-Clopidogrel

• Clopidogrel works by reducing the “stickiness” of platelets in a similar way to aspirin
• It is often recommended as an alternative for people who cannot take aspirin

Given Together In High-Risk Patients

• It may be recommended for people who have had a heart attack, a severe attack of angina, or who have undergone a coronary angioplasty & stenting.

Aspirin Resistance

• Resistance - Recurrent thrombosis while on antiplatelet therapy
  • The reported incidence of resistance varies greatly, from 5% to 75%
  • Although aspirin reduces the production of TXA2, it may fail to inhibit platelet aggregation because platelets continue to respond strongly to other agonists
  • TXA2-induced platelet aggregation is only one of the many factors leading to thrombus formation
    • It is the most common but not the only mechanism leading to ischemic events

Glycoprotein IIb/IIIa Receptor Inhibitors (Monoclonal Antibodies)

• Abciximab
• Tirofiban (non-peptide drug)
• Eptifibatide (peptide drug)
• GP IIb/IIIa receptor Blockers (antagonists)
• GPIIb/IIIa is found on the surface of platelets and is the most abundant receptor
• Activated, GPIIb/IIIa binds adhesive molecules, such as fibrinogen and vWF to promote clotting
• Abciximab binds to GPIIb/IIIa and stops the clot formation
• Given parenterally only (doesn't need to be activated by the liver)
  • Abciximab has a long half-life, while Tirofiban & Eptifibatide have short half-lives.
• In acute MI patients
  • Administered IV as an adjuvant to angioplasty surgery for the prevention of ischemic complications of angioplasty
  • Can be given with heparin or aspirin
    • Using combinations will also increase bleeding risks
• Used to prevent thrombosis and vascular events in patients with acute coronary syndrome and during percutaneous coronary intervention ADRs
• Bleeding
• Thrombocytopenia (immune reaction)

Phosphodiesterase (PDE) Inhibitor

• Dipyridamole
• Vasodilator
• Inhibits platelet function by inhibiting adenosine uptake
• Inhibits cAMP metabolism by inhibiting phosphodiesterase activity
• CAMP leads to anti-platelet action
• Cilostazol
• Phosphodiesterase (PDE3) inhibitor, promotes vasodilation & inhibits platelet aggregation.
• Little to no beneficial effect given alone
• Given in combination with aspirin to prevent cerebrovascular ischemia
• Due to its vasodilatory properties, it should be used with caution in coronary problems because vasodilation will cause reflex tachycardia
• Clopidogrel is a better choice
• Cilostazol is used for the prevention of intermittent claudication
  • Which represents muscle ischaemia during exercise caused by obstruction to arterial flow