[Music] welcome to this presentation on anti-thrombotic agents after completing this session you should be able to describe the usage and effects of anti-platelets and outline how anti-platelets may affect your practice and the patient's cardiac status and care before we start talking about antithrombotic agents it would be helpful to know what is involved in thrombus formation let's begin by discussing the process of hemostasis hemostasis is the biological process that causes bleeding to stop after injury to a blood vessel has taken place hemostasis involves the interaction of substances that promote clot formation as well as those which inhibit clot formation and promote clot breakdown next we'll look at the underlying mechanism of thrombosis in the body hemostasis consists of both pro-aggregatory and anti-aggregatory components that have to be kept in a finely tuned balance the pro-aggregatory system protects us from vascular damage and reduces the risk of bleeding to death by facilitating the formation of clots or thrombi and thereby limiting potential hemorrhage on the other hand the anti-aggregatory system protects us from over-coagulation and clot formation which if left unchecked would limit blood flow and lead to tissue and cell death so we see that the pro-aggregatory and anti-aggregatory systems complement one another to achieve this balance required for hemostasis to take place let's take a look at anti-platelet agents anti-platelet agents inhibit platelet function at various sites along the platelet activation and aggregation pathway there are two general pathways of clot formation the white clot pathway which involves platelet activation and aggregation and the red clot pathway which involves the coagulation cascade anti-platelet agents primarily affect the white clot or platelet pathway both pathways are involved in the formation of a clot or thrombus thrombus formation involves the interplay of both platelet activation as well as the coagulation cascade thrombus formation occurs in three basic steps first circulating blood is exposed to a thrombogenic surface such as a damaged vascular endothelium resulting from a ruptured atherosclerotic plaque second a series of events involving platelet adhesion activation and aggregation begin to take place along with the release of substances that further promote aggregation and cause vasoconstriction thirdly there is the triggering of the clotting cascade in this slide we see the various indications for anti-platelet agents these include unstable angina stable angina acute myocardial infarction post mi prophylaxis post coronary artery bypass graft or cabbage surgery post-coronary angioplasty coronary stents when combined with another anti-platelet agent such as clopidogrel or ticagrelor lone atrial fibrillation in persons under 65 years old transient ischemic attacks and non-hemorrhagic cerebral stroke in this slide we see the pathways of thrombus formation including both the clotting cascade on the left and the platelet pathway on the right in this slide take note of the various locations that the anti-platelet agents act see how aspirin blocks the formation of thromboxane a2 aspirin or derivatives of it have been in use for centuries in around 400 bc hippocrates treated his patients for pain with willow bark which contains salicylic acid from which aspirin was derived in 1763 reverend stone of chipping norton described the benefit of willow bark for treating ague or fever and shivering in 1853 von gerhart of the bayer drug company developed aspirin then felix hoffman a bayer chemist treated his father for rheumatism with aspirin in 1899 between 1948 to 1954 lawrence craven treated approximately 1 500 healthy overweight sedentary men from ages 40 to 65 years old with aspirin and it was found that for five years none of them experienced a cardiac event aspirin also known as acetylsalicylic acid or asa works to decrease platelet aggregation by irreversibly inhibiting the cyclooxygenase or cox enzyme the cox enzyme is necessary for the production of thromboxane a2 and thromboxane a2 is an agent that strongly promotes platelet aggregation and vasoconstriction by inhibiting the cox enzyme aspirin effectively reduces platelet aggregation impairing thrombus formation the conversion of thromboxane a2 and platelet aggregation can be initiated by several substances when the endothelial and smooth muscle cells are stimulated by injury they trigger the activation of the cox enzyme to increase production of prostacyclin prostacyclin is a powerful inhibitor of platelet aggregation and is a potent vasodilator by inhibiting the cox enzyme aspirin also reduces the formation of prostacyclin within the vessel walls this is actually an undesirable effect of aspirin when given at low dosages such as 81 milligrams daily aspirin inhibits the formation of thromboxane a2 and thus inhibits platelet aggregation without having much impact on the production of prostacyclin aspirin is indicated for the treatment of unstable angina stable angina acute mi post mi as secondary prevention silent ischemia post coronary artery bypass graft or cabbage surgery post-coronary angioplasty and stenting lone atrial fibrillation bioprosthetic valves transient ischemic attacks or tias post non-hemorrhagic strokes as secondary prevention and for primary prevention in patients over the age of 50 with diabetes and at least one other cardiac risk factor when aspirin is dosed once per day for cardiovascular indications it is recommended at a dose of 75 to 325 milligrams per day however only the 81 and 325 milligram tablets are available for purchase in canada low-dose aspirin inhibits thromboxane a2 generation and thus platelet aggregation without much impact on prostacyclin it is recommended that the dose does not exceed 325 milligrams per day adverse effects include gastric dyspepsia abdominal pain gastric hemorrhage as well as an overall increased risk of bleeding next we'll talk about situations which may result in a decreased response to aspirin the regular use of nsaids such as ibuprofen or naproxen blocks aspirin's anti-platelet actions smoking cigarettes enhances platelet function promoting platelet aggregation shortly after having a coronary artery bypass graft the body is in a highly thrombogenic state to recover from the invasive surgery and aspirin alone is insufficient to adequately inhibit platelet aggregation high levels of norepinephrine such as during emotional or physical stress can enhance platelet aggregation hyperlipidemia enhances platelet aggregation in addition high levels of ldl cholesterol may inhibit the effects of aspirin genetic variances also may result in hypercoagulability or aspirin resistance in addition to its cardiovascular protective benefits aspirin has other useful effects aspirin produces analgesia or pain relief by blocking prostaglandin synthesis in the central nervous system it also has an anti-inflammatory effect by inhibiting prostaglandin synthesis at the site of injury as well as inhibiting the actions of other pro-inflammatory mediators aspirin also relieves fever by decreasing prostaglandin synthesis and action within the hypothalamus next we'll take a look at the class of antiplatelet agents known as phyinopyridines take note of where the thianopyridines act on the platelet activation pathway these agents prevent platelet aggregation by binding to the adp receptor blocking the activation of the gp2b3a complex let's take a look at a couple thianopyridine agents clopidogryl is a thianopyridine which replaced ticlopidine as it was four times less likely to cause adverse effects as a thianopyridine it inhibits platelet aggregation by inhibiting adp induced platelet activation and platelet fibrinogen binding it is indicated for the reduction of atherosclerotic events such as mi stroke and cardiovascular death in patients with atherosclerosis and recent stroke acute coronary syndromes percutaneous coronary interventions acute mi and aspirin resistance adverse effects of clopidogrel include dyspepsia abdominal pain gastric hemorrhage and an overall increased risk of bleeding clopidogrel has a significant interaction with pantoprazole which reduces its effectiveness this interaction is not seen with other antacid therapy ticagrelor is the most recent addition to the thiano-pyridine class like clopidogrel it inhibits platelet aggregation by preventing adp-induced platelet activation and fibrinogen binding ticagrelor is indicated for reducing the risk of mi stroke and cardiovascular death in patients with acute coronary syndromes and those with the prior history of myocardial infarction like clopidogrel has the potential to cause gastric dyspepsia abdominal pain gastric hemorrhage and increases the risk of bleeding in terms of drug interactions ticagrelor may be used with aspirin but only at a low dose since higher doses impair to kagalore's antiplatelet effects ticagrelor also interacts with the torvastatin by increasing the drug levels of atorvastatin another antiplatelet agent is dipyridamole it is mostly used in combination with aspirin or warfarin depending on the indication for its use diperytomol inhibits platelet aggregation by allowing adenosine-like peptides to build up in the body in turn these peptides go on to inhibit platelet aggregation and may even produce vasodilation of the coronary arteries dipyridamole is indicated for the prevention of thrombosis in patients with prosthetic heart valves when used in combination with warfarin and it is indicated for the reduction of stroke or tia when combined with aspirin in stroke patients in terms of adverse effects of dipyridamole it may increase the risk of ischemia and angina due to coronary steel normally ischemic areas are dilated to compensate for coronary artery narrowing or stenosis however dipyridamole dilates healthy coronary arteries stealing away blood from the ischemic stenotic for this reason dipyridamole is contraindicated in unstable angina and immediately post acute mi patients in addition to its therapeutic indications dipyridamole is also used for diagnostic purposes as a pharmacological stress test agent it is used when patients are unable to perform an exercise stress test this stress test using dipyridamole or persanteen is called by the persanteen mibi as mentioned previously dipyridamole causes coronary steel by dilating only healthy coronary arteries and consequently reducing blood flow to ischemic arteries when the patient is examined with nuclear imaging the ischemic areas show up as cold spots representing decreased perfusion pharmacologic stress tests can be performed with either echo or nuclear imaging studies here we see the platelet adhesion and activation pathway once again the final group of drugs that we'll be discussing are the gp2b 3a inhibitors note how these medications block the final step of the platelet aggregation pathway gp stands for glycoprotein in this slide we'll be taking a closer look at gp2b 3a inhibitors these agents are the most effective anti-platelet agents because they reversibly inhibit the final common pathway of platelet aggregation this critical pathway of platelet aggregation involves the binding of activated platelet gp2b 3a receptors to fibrinogen and von willebrand factor by blocking this pathway these drugs prevent platelets from sticking to one another thus impairing the formation of the hemostatic plug there are approximately 75 000 gp2b3a receptors on the surface of each platelet blockade of these receptors prevents platelet aggregation caused by thrombin thromboxane a2 adp collagen and catecholamines and shear induced platelet aggregation intravenous gp2b3a receptor antagonists include abscixamab eptifibatide and terophaban adverse effects of these agents include prolonged bleeding time requiring platelet counts to be checked before and after administration mucosal membrane bleeding increased bleeding at arterial access sites especially in patients receiving heparin therapy therefore low-dose weight-adjusted heparin regimens are used absycomab only deactivates platelets that are in the body at the time of administration thus newly infused platelets are unaffected oral agents have a systemic or body-wide effect which can only be treated with hemodialysis this makes for a major drawback to using these agents orally let's take a look at the particular gp2b 3a blockers absycsimab or riopro is indicated for patients with acute coronary syndrome who are planned for pci and differs with respect to drug timing depending on whether it is being used in unstable angina and and stemi patients versus stemi patients for unstable angina or n stemi patients give 0.25 milligrams per kilogram iv bolus 10 to 60 minutes prior to pci followed by a continuous iv infusion run at 0.125 micrograms per kilogram per minute to a maximum rate of 10 micrograms per minute for 18 to 24 hours stopping one hour after pci for stemi patients give the bolus dose right at the time of pci followed by the continuous iv infusion run at the same rate as for n stemi patients except that it is run for 12 hours in stemi patients aspirin 325 milligrams is continued and iv heparin is added to keep the activated partial thromboplastin time or aptt between 60 to 85 seconds during epsimab infusion when done in this fashion epsimav results in reduced morbidity and mortality in terms of adverse effects you may see increased bleeding especially at mucous membranes and iv axis sites as well as thrombocytopenia which refers to an abnormally low number of platelets for this reason it is prudent to check the platelet count before starting therapy two to four hours after giving the bolus and 24 hours prior to discharging the patient the next agent we'll discuss is eptifibetide or integrillin it is indicated for the use in acs patients undergoing pci it is given as a 180 microgram per kilogram bolus up to a maximum of 22.6 milligrams administered immediately before the initiation of pci followed by a continuous infusion of 2 micrograms per kilogram per minute to a maximum of 15 milligrams per hour a second 180 microgram per kilogram bolus also to a maximum of 22.6 milligrams should be administered 10 minutes after the first bolus the infusion should be continued until hospital discharge or for up to 18 to 24 hours whichever comes first this therapy also reduced morbidity and mortality in these patients adverse effects of eptophibitide include bleeding of mucous membranes and axis sites accumulation in renal disease warranting a dose reduction in renal disease and thrombocytopenia warranting checking of the platelets the last drug we'll be discussing is terophaban also known as agrostat it is given as a bolus loading dose of 25 micrograms per kilogram administered over 5 minutes or less at the time of pci followed by a continuous iv infusion run at 0.15 micrograms per kilogram per minute continued for up to 18 hours adverse effects are similar to eptophibitide terophaban also requires dosage adjustment in renal dysfunction before this session comes to a close let's take some time to check the concepts we've covered how would an antiplatelet drug like aspirin be useful in the prevention of myocardial infarction pause the lecture and think about how myocardial infarctions occur and how aspirin works before moving on aspirin is useful in the prevention of mi because it decreases platelet aggregation this leads to decreased clot formation within the coronary arteries where atherosclerotic plaques are known to form in patients with coronary artery disease this leads to decreased risk of mi why are aspirin and clopidogrel used together during the first 1 to 12 months in post-mi patients during the initial months after a myocardial infarction the patient is at a greatly increased clot risk although aspirin and clopidogrel are both anti-platelet agents they work by different mechanisms this means they complement one another and further decrease the thrombotic risk during these especially thrombogenic months post mi that takes us to the end of this presentation on anti-thrombotic agents [Music]