Antiplatelet Medications and Hemostasis

• The pharmacology of blood involves antiplatelets, anticoagulants, thrombolytics, and drugs for anemia
• Objectives include mechanisms of hemostasis, platelets activation, antiplatelet drugs, anticoagulants, thrombolytics, and agents for anemia

Hemostasis and Platelets

• Hemostasis involves platelets in vascular repair and blood clot formation
• Primary hemostasis initiates a response to vascular injury
• In primary hemostasis, platelets adhere, activate, and aggregate to form a temporary plug
• Key mediators in primary hemostasis are von Willebrand factor (vWF), ADP, and thromboxane A2 (TXA2)
• Secondary hemostasis reinforces the platelet plug with a fibrin mesh
• The coagulation cascade leads to thrombin activation and fibrin clot formation
• Key factors in secondary hemostasis are coagulation factors, thrombin, and fibrinogen

Platelet Activation and Antiplatelet Drugs

• In damaged blood vessels, activated platelets form clots to prevent excessive bleeding
• Adhesion occurs when endothelial injury exposes proteins like collagen and vWF
• Platelets bind to vWF via glycoprotein (GP) Ib/IX/V receptor, anchoring them to the injury site
• Platelets release granules containing ADP, thromboxane A2 (TXA2), serotonin, and signaling molecules
• These released signals activate more platelets through P2Y12 (ADP) and thromboxane receptors
• Activated platelets express GPIIb/IIIa receptors to bind fibrinogen
• Fibrinogen links platelets together, forming a stable plug that is reinforced by fibrin in secondary hemostasis
• Antiplatelet drugs inhibit platelet aggregation, preventing arterial thrombi and lowering clot-related risks
• Blood clotting is a process involving circulating proteins and platelet activation after blood vessel damage
• Exposed collagen and von Willebrand factor lead to platelet activation and plug formation
• The plug is solidified by a fibrin meshwork through platelet activators
• Platelet activators such as adenosine diphosphate (ADP), serotonin, and thromboxane A2, are key to plug formation
• Thromboxane A2 is synthesized by COX enzymes, especially COX-1
• Aspirin counters platelet aggregation by targeting COX enzymes and P2Y12 ADP receptors Other drugs such as abciximab, eptifibatide, and tirofiban inhibit GPIIb/IIIa receptors, blocking fibrinogen binding
• Phosphodiesterase inhibitors like dipyridamole and cilostazol increase cAMP, disrupting platelet function and causing arterial dilation

Antiplatelet Drug Classes

• Aspirin inhibits the COX-1 enzyme, reducing thromboxane A2 and platelet aggregation, preventing cardiovascular events
• Aspirin's inhibitory effect is rapid, lasting 7-10 days, which is the lifespan of a platelet
• Side effects of Asprin being gastrointestinal irritation, bleeding and ulceration
• P2Y12 Inhibitors, like clopidogrel and ticagrelor, reduce platelet activation and aggregation, effective for acute coronary syndrome and stroke prevention
• P2Y12 Inhibitors side effects: bleeding and gastrointestinal disturbance
• Aspirin and clopidogrel are common oral medications
• Glycoprotein IIb/IIIa Inhibitors, such as abciximab and tirofiban, prevent fibrinogen
• Abciximab and tirofiban are frequently used intravenously
• Phosphodiesterase Inhibitors, like dipyridamole, prevent stroke and TIA by inhibiting platelet aggregation and vasodilation, often used with aspirin
• Phosphodiesterase Inhibitors side effects include headache, dizziness, gastrointestinal issues from phosphodiesterase

Anticoagulants

• Anticoagulants inhibit the coagulation cascade, preventing clot formation and growth
• Anticoagulants differ from antiplatelets by acting on clotting factors, reducing fibrin formation

Anticoagulant Drug Classes

• Vitamin K Antagonists (VKAS) such as Warfarin, inhibiting vitamin K-dependent clotting factors: II, VII, IX, X
• The International Normalized Ratio is the standard by which the anticoagulant activity of warfarin therapy is monitored
• Oral
• Unfractionated Heparin (UFH) enhances antithrombin III, inhibiting thrombin (factor IIa) and factor Xa
• Lower molecular weight heparins such as Enoxaprin and Dalteparin are effective due to being to more selectively inhibit factor Xa than UFH.
• Subcutaneous
• Factor Xa and thrombin inhibitors (DTIs) are two more anticoagulant drugs that exist

Heparins: Unfractionated vs. Fractionated

• Unfractionated Heparin (UFH) has a large, variable molecular weight
• Fractionated Heparin (LMWH) has a smaller, more uniform size
• UFH inhibits both Factor IIa (thrombin) and Factor Xa equally by enhancing antithrombin III, while LMWH preferentially inhibits Factor Xa
• UFH has lower bioavailability while LMWH is higher with predictable effects in factor Xa inhibition.
• Monitoring for UFH is requires aPtt monitoring
• Renal clearance for UFH is minimal
• Renal clearance for LMWH is a renal excretion

Thrombolytics and Anemia Drugs

• Selected patients with acute thromboembolic disease can be treated with thrombolytics.
• Thrombolytics convert plasminogen to plasmin
• Plasmin is a serine protease that dissolves clots.
• Thrombolytics used with caution with IV line with physician permission
• Alteplase, Streptokinase, and Tenecteplase are frequently used thrombolytics
• Anemia is characterized by reduced red blood cells or low hemoglobin content resulting in fatigue, palpitations, shortness of breath, pallor, dizziness, and insomnia
• Symptoms of Anemia from include blood loss, bone marrow disorders, hemolysis, infections, and endocrine deficiencies

Agents to Treat Anemia

• Drug-induced anemia due to toxic effects on blood cells from erythropoiesis
• Nutritional anemias arise from deficiencies of iron, folic acid, or vitamin B12
• Mild-to-moderate anemias using agents like iron, folic acid, vitamin B12, and erythropoiesis-stimulating agents
• Iron supplements replace necessary iron stores
• Ferrous sulfate, Iron dextran, and Ferrous gluconate are commonly used
• Side effects: GI upset, black stools, potential toxicity
• Vitamin B12 (Cobalamin) is necessary for DNA synthesis and maturation of red blood cells
• Side effects: rare allergic reactions, injection side reactions
• Folic acid is necessary for DNA synthesis and red blood cell production
• Folic acid and folinic acid are commonly used
• A side effect of folic acid is well-tolerated
• Erythropoiesis-Stimulating Agents (ESAs) stimulates RB cell production in the bone marrow such as Parental chemoTherapy
• Hydroxyurea reduces sickle cell crises
• Indication: a reduced sickle cell crisis
• Side effects: Bone marrow suppression, and gastrointestinal effects
• Iron Chelators bind excess iron to prevent toxicity in conditions such as thalassemia
• Side Effects: include liver toxicity and vision for iron chelators

This lesson covers antiplatelet medications like GPIIb/IIIa inhibitors and P2Y12 inhibitors used post-PCI and in ACS. It explores mechanisms of action, distinguishing characteristics of drugs like Ticagrelor vs. Clopidogrel, and the process of primary hemostasis.