Introduction to Antithrombotic Medications

Introduction to Antithrombotic and Antiplatelet Medications

• Overview of antithrombotic and antiplatelet medications
• Presented by Dr. Mitchell Lai, Department of Pharmacology, National University of Singapore.

Haemostasis

• Haemostasis is the process of stopping bleeding.
• Phases of haemostasis:
  • Vasoconstriction (vascular spasm)
  • Platelet plug formation (adhesion, activation, aggregation)
  • Fibrin formation

Anticlotting Drugs

• Categorization of anticlotting drugs:
  • Antiplatelet drugs
  • Anticoagulants
  • Thrombolytics

Antiplatelet Drugs

• Non-steroidal anti-inflammatory drugs (Aspirin)
• Platelet GPIIB/IIIA receptor blockers (Abciximab, Eptifibatide, Tirofiban)
• ADP receptor blockers (Ticlopidine, Clopidogrel)
• PDE inhibitor (Dipyridamole)

Platelet Activation and Aggregation

• Platelet activation involves a complex series of events triggered by damaged endothelium or collagen.
• Thromboxane A2 plays a key role in initiating platelet aggregation.
• Prostacyclin opposes platelet aggregation.
• Aspirin inhibits Thromboxane A2 synthesis.

Aspirin

• Actions: Inhibits cyclooxygenase, reducing Thromboxane A2 production thereby inhibiting platelet aggregation.
• Pharmacokinetics: Duration of effect is related to the life of the platelet, approximately 7-10 days.
• Clinical Uses: Prophylactic treatment of transient cerebral ischaemia, to reduce the incidence of recurrent myocardial infarction, to decrease post-myocardial infarction mortality.
• Adverse Effects: Bleeding, gastric upset, ulcers, gastrointestinal bleeding.

GP IIB/IIIA Receptors

• Glycoprotein (GP) IIb/IIIa is a platelet membrane protein involved in platelet aggregation.
• Activation of this receptor is the final common pathway for platelet aggregation.
• GP IIb/IIIa inhibitors (Abciximab, Eptifibatide, Tirofiban) are used during procedures.

Other Platelet Aggregation Inhibitors

• Clopidogrel and Ticlopidine act by blocking ADP receptors on platelets.
• Dipyridamole inhibits the breakdown of cAMP, thereby preventing platelet activation.

Anticoagulants

• Heparin derivatives
• Coumarin derivatives (warfarin)
• Lepirudin hirudin
• Antithrombin III

Thrombin

• Thrombin (factor IIa) plays a crucial role in the coagulation cascade.
• Thrombin activates other factors in the coagulation cascade, leading to fibrin formation and clot stabilization.
• It is important for platelet aggregation and cell proliferation.

Intrinsic and Extrinsic Pathways

• These are pathways involved in blood clotting.
• Heparin, along with other anticoagulants, inhibits the coagulation cascade and prevents or reduces clot formation.

Antithrombin III and Heparin

• Antithrombin III (ATIII) is an endogenous anticoagulant protein.
• Heparin enhances the action of ATIII on clotting factors to prevent or reduce clot formation.
• LMWHs (Low Molecular Weight Heparins) have better bioavailability and longer half-life.
• Heparin is a family of sulfated glycosaminoglycans.

Actions of Heparins

• Heparin binds to ATIII, causing a conformational change, exposing its active site, leading to inhibition of proteases (thrombin, Xa).

Heparin Clinical Uses

• Treatment of deep vein thrombosis, pulmonary embolism, myocardial infarction.
• Used in combination with thrombolytics for revascularization procedures and GPIIb/IIIa inhibitors during angioplasty and stenting.

Heparin Adverse Effects

• Haemorrhage (stop therapy + protamine sulfate)
• Thrombocytopenia

Vitamin K

• Vitamin K is a fat-soluble vitamin essential for the formation of clotting factors (II, VII, IX, X).
• Reduced vitamin K is a crucial cofactor in the carboxylation of glutamate residues.

Warfarin

• Warfarin is an anticoagulant that inhibits vitamin K epoxide reductase activity and prevents the carboxylation of vitamin K-dependent proteins.
• Clinical uses are similar to heparin but Warfarin is contraindicated in pregnancy.
• Pharmacokinetics: Elimination depends on hepatic cytochrome P450 metabolism.
• Adverse Effects: Bleeding, hemorrhagic disorder in the fetus.

Thrombolytic Agents

• t-PA (alteplase), Urokinase, Streptokinase, Anistreplase
• These are used to break down existing blood clots

Fibrinolytic System

• Thrombolytic agents activate the fibrinolytic system which leads to the degradation of fibrin, breaking down the blood clot.

Thrombolytic Agents Clinical Uses

• Emergency treatment of coronary artery thrombosis, peripheral arterial thrombosis, and emboli, ischaemic stroke (under 4.5 hours window).

Summary of Anticlotting Drugs

• Provides a comprehensive overview of the different classes of anticlotting drugs, their mechanisms of action, clinical uses, and adverse effects.

Medications for Coronary Ischemic Heart Disease

• Introduction to medications for Coronary Ischemic Heart Disease.
• Discusses different types of angina (atherosclerotic, vasospastic, unstable).

Types of Angina

• Atherosclerotic angina: Associated with plaque buildup.
• Vasospastic angina (Prinzmetal): Due to coronary artery spasm.
• Unstable angina (acute coronary syndrome): Sudden worsening of angina that can lead to a heart attack.

Determinants of Cardiac Oxygen Requirement

• Preload: Diastolic filling pressure of the heart, reliant on blood volume and venous tone
• Afterload: Resistance against ejection of blood, affected by arterial blood pressure.

Drug Therapy for Angina

• Vasodilators (including nitrates)
• Cardiac depressants (including β-blockers)
• Calcium channel blockers

Nitrates

• Mechanism of action: Nitrates cause vasodilation by stimulating the formation of cyclic GMP, relaxing vascular smooth muscle and thus reducing preload and afterload, and thus reducing pain and requirement for oxygen.

Glycerol Nitrates

• Nitroglycerin is a potent vasodilator, specifically targeted for acute treatment of angina.
• Administration methods: Sublingual for rapid relief, transdermal for more prolonged effect.

Isosorbide Dinitrate (ISDN)

• Pharmacokinetics: Longer duration of action in comparison to nitroglycerin.
• ISDN is administered orally, with sustained or immediate release forms available.

ISDN and ISMN Clinical Uses

• Prophylaxis for angina.
• For the treatment of heart failure.

Nitrates: Side Effects

• Baroreflex activation
• Reflex tachycardia
• Hypotension
• Headaches

β-Blockers

• MOA involves blocking β1 receptors in cardiac myocytes, decreasing heart rate and contractility, thus lowering oxygen demand.

Calcium Channel Blockers

• MOA involves preventing calcium from entering muscle cells, causing vasodilation and lowering blood pressure.
• Divided into two categories in relation to their structure: dihydropyridines (DHPs) and non-DHPs.

DHP Calcium Channel Blockers

• Clinical uses: Hypertension, stable angina, reducing myocardial infarction and stroke risk.
• Adverse Effects: Hypotension, heart failure, myocardial infarction,

Ivabradine

• Ivabradine is a unique heart rate-lowering drug.
• Indications: Stable angina, chronic heart failure.
• Mechanism of action: Specifically targets the If current in the sino-atrial node.

Concomitant Diseases and Drug Considerations

• Review of commonly used drugs for treating hypertension in conjunction with various diseases.