Anti-Platelet Agents PDF

# Anti-Platelet Agents - Molecules that do not allow platelets to aggregate and thus prevent clotting especially in the arteries. ## Anti-Platelet Agents - **Cyclooxygenase Inhibitors:** Aspirin - **PDE Inhibitors** - **ADP Receptor Antagonists** - Affect only one pathway in platelet activation....

# Anti-Platelet Agents - Molecules that do not allow platelets to aggregate and thus prevent clotting especially in the arteries. ## Anti-Platelet Agents - **Cyclooxygenase Inhibitors:** Aspirin - **PDE Inhibitors** - **ADP Receptor Antagonists** - Affect only one pathway in platelet activation. - Limited antiplatelet effect. - **GP IIb/IIIa Receptor Antagonists** - Block the final common step in platelet activation. - Powerful antiplatelet effects. ## Plaque Disruption A diagram showing the different stages of a platelet's interaction with a plaque. - **Plaque Disruption** - Collagen - vWF (von Willebrand factor) - **Platelet Adhesion and Secretion** - Aspirin - COX-1 (Cyclooxygenase-1) - TXA2 (Thromboxane A2) - ADP (Adenosine Diphosphate) - Ticlopidine - Clopidogrel - **Platelet Recruitment and Activation** - **GPIlb / Illa Activation** - Abciximab - Eptifibatide - Tirofiban - **Platelet Aggregation** ## Aspirin - **Mechanism:** - Irreversibly inhibits cyclooxygenase (COX) - COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins). - **Effect:** - Persists for 5-10 days. - Long acting because new proteins must be synthesized. - **Major Side Effects:** - Stomach problems and bleeding - can be life-threatening ## Actions of COX-1 and COX-2 A diagram showing the different actions of COX-1 and COX-2. - **COX (Cyclooxygenase)** - **COX-1:** (Produced throughout the body) - Produces thromboxane - Promotes vasoconstriction and platelet aggregation - **COX-2:** (Produced at sites of inflammation) - Produces prostacyclin - Prevents platelet aggregation and vasodilator. - **Balance is Essential** ## Pay Attention - **At a small dose (50-75mg/d), the drug inhibits the synthesis of TXA2.** - **At higher doses (> 320 mg/day), the drug inhibits the synthesis of PGI2.** ## Other NSAIDs - Shorter duration because of reversible competitive inhibitory action. - Naproxen, meclofenamic acid, Ibuprofen, Indomethacin, phenylbutazare. ## Contraindication - Patients with Glucose-6-PO4 dehydrogenase deficiency: induce hemolysis. ## Uses - Reduces the risk of VTE after orthopaedic surgery by 36%. - Significant reduction in DVT and PE. ## PDE Inhibitors: Dipyridamole - Used in combination with warfarin for postoperative primary prophylaxis of thromboemboli in patients with prosthetic heart valves. - Dose: 25mg TID Orally. ## ADP Receptor Antagonists: - Ticlopidine, Clopidogrel, Prasugrel - **Action:** - Irreversible blockade of ADP receptors on the platelet surface. - Prevent ADP-stimulated platelet aggregation. - **Uses:** - Stroke and acute coronary syndromes. - Used as an alternative for patients intolerant to aspirin. ## Clopidogrel - Oral antiplatelet drug. - **Pharmacokinetics:** - Orally active. - 50% bioavailable. - Prodrug. - **Clinical Use:** - Prevent blockage of coronary artery stents. - Reduce thrombotic events: - MI (Myocardial Infarction) - Ischemic stroke - Vascular death - **Adverse Effects:** - Similar to Aspirin. - Abdominal pain, dyspepsia, diarrhea and rash. - Less intracranial hemorrhage & less GI bleeding vs aspirin. - **Drug Interactions:** - Heparin. - Warfarin. - NSAIDs-Aspirin. ## Ticlopidine - Similar action as clopidogrel. - Prevention of thrombotic stroke. - **Life-threatening hematologic reactions:** - Neutropenia. - Agranulocytosis, etc. - Gl disturbances and dermatologic reactions. ## Prasugrel - Investigational drug. - Prodrug. ## Glycoprotein IIb/IIIa Receptor Antagonists - **Action:** - Activation of glycoprotein receptor on platelet membrane is the final common pathway for platelet aggregation. - The most effective antiplatelet drugs. - **Drugs:** - Abciximab - Tirofiban - Eptifibatide. - **Administration:** - Administered by IV. - **Effect:** - Reversible blockade of platelet GP IIb/IIIa receptors. - Inhibit the final step in aggregation. - Prevent aggregation stimulated by all factors. ## Clinical Uses - Prevent ischemic events: - Acute coronary syndromes (ACSs) - Percutaneous coronary intervention (PCI). ## Abciximab - **Mechanism:** - A purified Fab fragment of a monoclonal antibody. - **Side Effect:** - Risk of bleeding. ## Eptifibatide - **Mechanism:** - A small peptide drug. - **Side Effect:** - Risk of bleeding. ## Tirofiban - **Mechanism:** - Isolated from snake venom. - **Side Effect:** - Risk of bleeding. ## Antiplatelet Drugs: Interactions A table showing the interactions of antiplatelet drugs and other drugs. | **Interacting Drug** | **Effect of Interaction** | |---|---| | Aspirin and NSAIDs | Increased risk for bleeding | | Macrolide antibiotics | Increased effectiveness of anti-infection | | Digoxin | Decreased digoxin serum levels | | Phenytoin | Increased phenytoin serum levels | ## Fibrinolytic Drugs (Thrombolytic Agents) - These agents can activate the conversion of plasminogen to plasmin. - A serine protease that hydrolyzes fibrin and thus dissolves clots. - Mainly used in acute thrombolism. ## Include - **Plasminogen activator from the human body:** - Urokinase (UK) - Alteplase (t-PA) - **Plasminogen activator form bacteria:** - Streptokinase (SK) - Anistreplase - Stephylokinase - **Plasminogen activator from a snake:** - Snake venom antithrombus enzyme - Ancrod - Acutase ## Plasminogen Activation Diagram showing the various stages of Plasminogen activation: - **Activation** - Various stimuli - **Blood proactivator** - Blood activator - Antiactivators - t-PA, urokinase - Aminocaproic acid - Streptokinase - Activator - Proactivator - Anistreplase - Degradation Products - **Plasminogen** - **Plasmin** - Fibrinogen - Fibrin - Fibrin split products ## Shared Characteristics - **Action:** - All act either directly or indirectly to convert plasminogen to plasmin, which in turn cleaves fibrin, thus lysing thrombi. - **Clot dissolution occurs with a higher frequency when therapy is initiated early after clot formation.** ## Streptokinase (SK) - **Mechanism:** - Acts indirectly. - SK-plasminogen complex 'n activate plasminogen. - **Note:** Anti-streptococci antibodies will neutralize it. - **Action:** - Has similar affinity for free or bound plasminogen; no clot selectivity. - **Clinical uses:** - Thrombolytic therapy: early,< 6h - Intravenous route: DVT, multiple pulmonary emboli. - Intra-arterial route: myocardial infarction ## Urokinase (UK) - **Mechanism:** - Activating plasminogen directly. - **Dosage:** - Loading dose: 4500 u/kg given over 10 minutes followed by continuous infusion of 4500 u/kg every hour for 12 h. - **Clinical Uses:** - Same use as SK, especially cerebral embolism. - **Adverse Reactions:** - Bleeding, but no allergic reaction. ## Tissue Plasminogen Activator (t-PA) - Alteplase, reteplase, and tenecteplase - **Mechanism:** - Act directly, bind to fibrin in a clot and act locally to dissolve the clot. - **Effect & Note:** - Act selectively, risk of bleeding. - (High affinity to plasmnogen bound to fibrin in the embolism, low affinity to free plasmnogen). - **Benefits:** - Superior to SK and UK. - **Uses:** - Mainly in acute myocardial infarction to dissolve clots. ## Anistreplase (Anisoylated Plasminogen Streptokinase Activator Complex) - **Mechanism:** - A complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme's active site. - When administered, the acyl group spontaneously hydrolyzes, activating streptokinase-proactivator complex. - **Effect:** - Greater clot selectivity (ie, more activity on plasminogen associated with clots than on free plasminogen in the blood). ## Adverse Effects - **Bleeding:** Fibrinolytic drugs may lyse both normal and pathologic thrombi. - Bleeding can be controlled by Aminocaproic acid (inhibits plasminogen activation). - **Hypersensitivity reaction:** Streptokinase. - **Arrhythmias (bradycardia,tachycardia):** Free radicals generated after fibrinolysis. - **Hypotension:** Streptokinase. ## Thrombolytic Drugs: Contraindications/Precautions and Interactions - **Contraindicated in patients:** - Active bleeding, history of stroke, aneurysm, recent intracranial surgery. - **Used cautiously in patients:** - Recently undergone major surgery. - With hypertension, diabetic retinopathy, any condition - bleeding significant possibility. ## Thrombolytic Drug Summary A table comparing the properties of different Thrombolytic drugs: | **Cost** | **Dosing Administration** | **Average Dose** | **Potential Antigenicity** | **Fibrin Specificity** | **Enzymatic Efficiency for Clot Lysis** | **Drug** | |---|---|---|---|---|---|---| | Low | 1 hr IV infusion | 1.5 MU | Yes | Minimal | High | Streptokinase | | Moderate | 2-5 min IV infusion | 30 u | Yes | Minimal | High | Anistreplase | | Moderate | 15 mg IV bolus, 50 mg over 30 min, then 35 mg over 60 min | 100 mg | No | Moderate | High | Tissue plasminogen activator | | High | 1 mu IV bolus, 1 mu over 60 min | 2 mu | No | Moderate | Low | Urokinase | ## Drugs Used to Reduce Clotting A table summarizing different drug classes used to reduce clotting. | **Drug Class** | **Prototype** | **Action** | **Effect** | |---|---|---|---| | Anticoagulant | Parenteral | Heparin | Inactivation of clotting factors | Prevent DVT | | | Oral | Warfarin | Decrease synthesis of clotting factors | Prevent DVT | | Antiplatelet | Aspirin | Decrease platelet aggregation | Prevent arterial thrombosis | | Thrombolytic | Streptokinase | Fibinolysis | Breakdown of thrombi | # Anti-Anemic Drugs - **Haematopoiesis:** The production of erythrocytes, platelets, and leukocytes from undifferentiated stem cells. - The haemtopoietic machinary reside in the bone marrow in adults. - It requires a constant supply of essential nutrients: - Iron - Vit B12 - Folic acid - Presence of hematopoietic growth factors ## Anemia - **Definition:** A decrease in the circulating RBC mass. - **Usual Criteria:** - Hb of less than 12g/dl in women. - Hb of less than 14g/dl in men. - **Causes:** - Acquired or hereditary abnormality of RBCs or its precursor. - A manifestation of an underlying non-hematologic disorder. ## Classification of Anemia - **Anemia associated with decreased RBC production:** - Iron deficiency - Megaloblastic - Thalassemia - Anemia due to chronic disease and renal failure. - **Anemia due to increased RBC destruction:** - Hemolytic - Sickle cell ## Introduction: Iron - **Total quantity of iron in the body:** 4-5g. - **Distribution:** - 65-70% in the form of Hb in RBC. - 4% in myoglobin. - 1% in various heme compound. - **Storage:** - 15-30% stored in the form of ferritin and hemosiderin in reticuloendothelial system, liver, spleen, intestinal mucosa, and bone marrow. ## Iron's Role in the Body - **Required for Hb production.** - **In the absence of adequate iron:** - Small red cells with insufficient Hb are formed, giving rise to microcytic hypochromic anemia. - **Vit B12 and folic acid are required for normal DNA synthesis.** ## Iron Deficiency - **Chief source of iron:** Meat. - **Causes:** - Inadequate dietary intake, seen in vegetarians and malnourished pts. - Blood loss in women with heavy menstruation. - Increased iron requirement during pregnancy and in growing children. - **Most common cause of iron deficiency anemia in adults:** Blood loss. - **Iron forms **heme**, which combined with proteins **globin** and form **hemoglobin**. - **Hb binds **oxygen** (in the lungs) and transports it in the tissues.** ## Anti Anemic Drugs: Iron Preparations - **Oral iron:** - Ferrous sulfate: 325mg - 65mg elemental iron. - Ferrous gluconate: 320mg -37mg elemental iron. - Ferrous fumarate: 325mg - 106mg elemental iron. - **Parenteral Iron.** - **Note:** Iron is only used in iron deficiency anemia. ## Pharmacokinetics of Iron - **Absorption:** Iron (Fe2+) absorbed in Fe3+ (ferric). - Ferric iron binds with transferrin in plasma and transported in other tissues and stored as ferritin and hemosiderin form. - **Absorption percentage of dietary iron:** 10-20%. - **Increased absorption occurs with iron requirements:** Pregnancy, menstruation, and growing children. ## Pharmacokinetics of Iron Continued - **Absorption:** Fe2+ (ferrous iron). - **Increased by:** Vitamin C, amino acid, and gastric acid. - **Decreased by:** phosphorus, calcium, Tannic acid, Antacids, H2-receptor blockers, Proton pump inhibitors, Tetracyclines. - **Elimination:** - Minimal amount (about 1mg/day) are lost in sweat, saliva, and in exfoliated skin and intestinal mucosal cells.