Anti-platelets PDF

Not all blood thinners are anticoagulants 3 ways basically to get the blood thin ○ Destroying the activity of platelets (anti-platelets)- the mature form of keratocytes in bone marrow- precursor ○ Coagulation factors to work on that primer that is already the...

Not all blood thinners are anticoagulants 3 ways basically to get the blood thin ○ Destroying the activity of platelets (anti-platelets)- the mature form of keratocytes in bone marrow- precursor ○ Coagulation factors to work on that primer that is already there and inhibit that process (anti-coagulants) ○ Balancing the part where there is bleeding to seal off whatever was started (thrombus) = clot (break the clot- thrombolytics) Hemostasis Process of the arrest of bleeding in the hypo-coagulation state (primarily from injury to stop the bleeding) Prevents and stops bleeding, or hemorrhaging Complex interaction b/w the vascular system, platelets, and various proteins and factors in the blood to form a clot After the bleeding stops, the clot is eventually removed through a process called fibrinolysis- the clot is broken down and tissue is repaired Crucial for maintaining blood volume and pressure ○ Trauma w/ heavy bleeding can lead to organ failure so important to maintain BP Deficiencies or disorders in this process- bleeding disorders or thrombosis (excessive clotting) ○ Thrombotic Thrombocytopenic Purpura (TPP) The increased clotting that occurs in TTP also uses up your platelets. TTP occurs when you do not have the right amount of an enzyme (a type of protein in your blood) called ADAMTS13. This enzyme controls how your blood clots. If you do not have enough ADAMTS13, your body makes too many blood clots. In acquired TTP, the ADAMTS13 gene is not faulty. Instead, your body makes antibodies (proteins) that stop the ADAMTS13 enzyme from working properly ○ Von Willebrand’s disease (said he would ask this)- hypocoagulation and AD disorder; has a dual role in hemostasis VWF deficiency or dysfunction leading to defects in primary hemostasis as VWF promotes adhesion and aggregation VWF also plays a role in the secondary hemostasis as it acts as chaperone protein for factor VIII (FVIII), protecting it from degradation and clearance in the circulation and in VWF disease, Factor VIII clotting activity decreased VWF acts as a carrier protein for factor VIII (FVIII), protecting it from premature degradation. This is crucial because FVIII is essential for the coagulation cascade, specifically in the conversion of prothrombin to thrombin. Tests will show normal platelet count with slightly prolonged PTT Processes involved Vascular spasm (vasoconstriction): blood vessels constrict to reduce blood flow and minimize blood loss ○ Trauma centers look at this Platelet (plug formation): platelets adhere to the site of injury (induced by collagen exposure that comes from vascular wall- has elasticity) and become activated, releasing substances that attract more platelets to the area (platelet aggregation)- forms a temporary “plug” ○ When the vascular wall is damaged, collagen is exposed. Platelets adhere to this collagen via receptors, primarily glycoprotein Ib (GpIb) binding to vWF, which is anchored to the collagen ○ Adhered platelets become activated, changing shape and releasing various substances (like ADP, thromboxane A2, and serotonin) that attract more platelets ○ This recruitment leads to platelet aggregation, where more platelets stick together, forming a temporary “plug” that covers the injury site Coagulation (clotting): clotting factors are activated in a cascade fashion, leading to the conversion of fibrinogen (a soluble plasma protein) into fibrin (an insoluble protein)- fibrin strands weave through the platelet plug, stabilizing the clot ○ Produced in the liver and go to the site of injury ○ Does not end here, once the fibrin formation is a sustained plug… we have to dissolve the plug Stages Primary Hemostasis (get that temporary plug out) ○ Vasoconstriction (vascular system) ○ Platelet exposure to subendothelial collagen of blood vessels -> adhesion ○ Platelet activation upon attachment: release of ADP, ATP, Thromboxane A2 (promotes vasoconstriction) -> activation of platelets that induces aggregation ○ Platelet aggregation, phospholipid provides a site for fibrin formation -> aggregation Secondary Hemostasis ○ Involves the coagulation cascade that leads to the formation of a stable fibrin clot ○ Cascade of events upon activation occur in the bloodstream at site of injury ○ Inactive clotting factors are produced in the liver ○ Coagulation cascade: Intrinsic Pathway Activated by damage to the blood vessel Involves factors XII, XI, IX, and VIII ○ Calcium is all cells is the “chip” to start the initiation of cascade events that leads to the formation of factor 10, forms 10a, and blah Extrinsic Pathway Initiated by tissue factor (TF) released from damage tissue Leads to the activation of Factor VII, which then activates Factor X  Common Pathway Both pathways converge (intrinsic and extrinsic) Lead here, leading to the conversion of prothrombin (Factor II) to thrombin (Factor IIa) Thrombin converts fibrinogen (Factor I) into fibrin (Factor Ia) ○ Fibrin formation Fibrin strands crosslinked and stabilize the platelet plug created during primary hemostasis This complex provides structural support and permanently seals the site of injury ○ Regulation and control Several regulatory factors ensure the process does not become excessive, preventing thrombosis Natural anticoagulants such as antithrombin, protein C, and protein S Counteracting substances Tertiary hemostasis ○ Dissolution of fibrin: clot systemically and gradually dissolved as the vessel heals ○ Dependent on plasminogen activation ○ Key components in the tertiary hemostasis Plasminogen (inactive form) Plasminogen activators Plasmin Fibrin Fibrin Degradation Products (FDP) Inhibitors of plasminogen activators and plasmin Activators of fibrinolysis Intrinsic activators ○ Factor XIIa, XIa, kallikrein Extrinsic activators ○ Tissue-type plasminogen activator (t-PA) ○ Urokinase-type plasminogen activator (u-PA) Exogenous activators ○ Streptokinase (derived from beta strep bacteria) Antiplatelets Antiplatelet agents are used both prophylactically and acutely in the setting of ACS to inhibit platelet activation &/or aggregation ○ Antiplatelets are used to treat for patients complaining of chest pain and if that patient needs to have an emergency angioplasty Main classes ○ Cyclooxygenase (COX-1) inhibitors Acetylsalicylic acid (aspirin) ASA is a prototype and the only one used  MOA: Irreversibly blocks cyclooxygenase (COX-1) activity by acetylating the enzyme (COX-1 IS ALWAYS ON and its production leads to thromboxane; inhibiting endogenous system) ○ More production of substrate will inhibit activity and get the inhibitor to work on what it needs to work = reversible; because this is irreversible** ○ inhibit cyclooxygenase (COX) and reduce prostaglandin synthesis, thereby reducing fever and relieving pain and inflammation ○ Ibuprofen is a derivative of Aspirin; it works on COX-1 and -2 Side effects involved in clotting factors that is always on which is COX-1 and can cause bleeding; people who are already prone to bleeding and taking NSAIDs may experience nose bleeds GI upset; COX-1 is involved in the prostaglandin lining in stomach and once inhibited leads to upset stomach Also blocks cyclooxygenase 2; not always on- only on upon inflammation that is called phospholipase 2 due to result of injury or infection Prevents the conversion of arachidonic acid to TXA2 in platelets ○ TXA2 promotes platelet aggregation and vasoconstriction ○ Specifically, COX are enzymes that convert arachidonic acid to prostaglandin and/or thromboxaneA2 Platelet-induced TXA2 synthesis (synthesis is production) is blocked for the life of the platelet (7-10 days) Added MOA: COX-1 inhibition also prevents the formation of PGI2 in vascular endothelium ○ PGI2 promotes vasodilation and inhibits platelet aggregation (this is a balancing act- cyclooxygenase that is always on promotes thromboxane and promotes formation of PGI2 to promote vasodilation BUT thromboxane has more activity and “wins” BUT PGI2 lasts longer and effect stronger) PGI2 = less clotting; TXA1 = more clotting TXA effect > PGI2 COX1 = causes more clotting ASA blocks TXA2 & PGI2; less clotting at TXA1 and more clotting in PGI2; net effect is less clotting  ○ Endothelium can regenerate COX-1 restoring PGI2 production within hours Net result is that aspirin preferentially inhibits TXA2, rather than PGI2, favoring vasodilation and inhibition of platelet aggregation Aspirin does not inhibit platelet adherence Dosing The recommended dose varies depending on indication Ranges from 81-325 mg/day (81 suffices for action) ○ Usual dose for ACS, acute MI, is 325 mg given immediately upon symptoms ○ Prophylactic dose ranges from 81-325 mg daily ○ Higher doses (more side effects) may decrease effectiveness due to decreased ability to regenerate PGI2 ○ 325 mg daily for chemoprevention (effects of chemo) ○ Higher doses used for anti-inflammatory, analgesic, and antipyretic indications Clinical pearl: state that we’re practicing in and optometrists that cannot use stage 3 or 4 narcotics, as long as you know where the pain will be targeted: Ibuprofen (600 mg) QID in combo w/ Tylenol (650 mg) q 8 hr QID Good additive effect and for acute pain; no kidney or liver issues, no aspirin allergy; short course of treatment Adverse effects of ASA in response to PGE2 and TX inhibition are dose-dependent GI effects (due to PGE2 inhibition) ○ Abdominal pain ○ Heartburn ○ Nausea ○ GI ulceration and bleeding  COX-2 inhibitors are of major clinical interest as these have been related to lower incidence of gastrointestinal bleeding. Both COX-1 and 2 inhibitors can cause sodium retention and reduction of the glomerular filtration rate. Fetal COX-2 inhibition can be responsible for neonatal chronic renal failure and therefore maternal usage should be avoided until further studies confirm the safety of this group of drugs. Bleeding (due to inhibition of TXA2) ○ D/c 7 days prior to elective surgery because it can cause excessive bleeding ○ Cataract surgery; stay off these as it can cause corneal bleeding Renal dysfunction (due to inhibition of renal PGs) ○ Progressive dysfunction w/ chronic use; Has anti-inflammatory effect so renal arteries are vasoconstriction and can lead to renal dysfunction Exacerbation of asthma (due to shifting of AA metabolism to lipoxygenase pathway) ○ Increases LT formation which are known inflammatory mediators in asthma ○ inhibition of the COX pathway activates the lipoxygenase pathway, leading to increased leukotriene synthesis and risk of bronchospasms or asthma exacerbation ○ Arachidonic acid pathway Other adverse effects: ○ Tinnitus, headache, dizziness, confusion, hearing loss, and metabolic acidosis due to salicylate toxicity Aspirin toxicity can cause dim vision and yellow tint ○ Hypersensitivity reactions ranging from rash to angioedema to anaphylaxis  ○ Reye syndrome - do not administer to children under the age of 16 (< 12 highly contraindicated; tylenol is given) hypersensitivity reaction that causes swelling in the liver (elevated liver enzymes) and brain. It can occur at any age but usually affects children and teenagers after a viral infection, most commonly the flu or chickenpox ○ Avoid during pregnancy (esp. during 3rd trimester): prolonged labor, increased risk for antepartum and postpartum hemorrhage ○ Phosphodiesterase (PDE) inhibitors more used for patients w/ peripheral artery disease because they’re diabetics Dipyridamole (common) MOA: ○ Inhibits phosphodiesterase (PDE) which results in increased cAMP and inhibition of platelet aggregation ○ Increased cAMP also results in vasodilation, most of them do this (increase production of nitric oxide = vasodilation) ○ Blocks the adenosine transporters on platelets, leading to increased levels of adenosine in the bloodstream: resulting in enhanced platelet inhibition since adenosine can inhibit platelet aggregation ○ Increased adenosine levels in the bloodstream improve blood flow ○ PDE type 3 is involved here; Plavix is used a lot Clinical use ○ Adjunct tx w/ anticoagulants (Warfarin- not used first line but can be done) in patients w/ prosthetic heart valves who cannot take aspirin Heart valves can be derived artificially and induce breakage of blood vessels and formation of clots so they must have some anticoagulant ○ Cardiac stress testing- use for this indicates declining as adenosine is being used Some people need a chemical stimulant to monitor levels of oxygenation. Adenosine can be used to incite the same thing as exercise for those who cannot do exercise. Usual dose ○ 75-100 mg QID (PO) Adverse effects ○ Exacerbation of angina following IV administration during stress testing ○ Hypotension (IV) because of vasodilation  ○ GI upset (PO) ○ Dizziness (PO) Drug interactions ○ Increased risk for bleeding when given in combo. w/ aspirin and other anti-platelets or anticoagulants ○ Theophylline Patients on theophylline may require higher doses of dipyridamole during stress testing (hold theo for 36 hours prior to test) Dipyridamole/ASA combination (Aggrenox) Aggrenox is a combination of 25 mg Aspirin and 200 mg Dipyridamole in a sustained-release formulation to be taken twice daily Approved for use to reduce risk of stroke in patients w/ trans ischemic attacks or w/ hx of thrombotic stroke Adverse effects and drug interactions are a combination of those seen w/ ASA and dipyridamole individually Cilostazol (Pletal) DOC to treat PAD A quinolinone derivative that has been used for peripheral artery disease ○ Quinolones are commonly used to treat bacterial infections and are known for their mechanism of action, which typically involves inhibiting bacterial DNA gyrase and topoisomerase IV MOA: ○ Inhibits cellular phosphodiesterase, particularly phosphodiesterase III (PDE III) leading to increased levels of cAMP cAMP causes vasodilation and inhibition of platelet aggregation Clinical use: ○ Indicated to reduce symptoms of intermittent claudication (increases walking distance) Someone who comes in and complains of walking fine at home but walking for a while muscles cramp and experiences pain. Amount of stenosis that is occurring in lower limbs causing a deficiency in oxygen = pain. Intermittent claudication is a primary symptom in peripheral artery disease Usual dose: ○ 100 mg PO BID ½ hour before, or two hours after meals Take on empty stomach  ○ Decrease to 50 mg PO BID if given concurrently w/ CYP inhibitors CYP inhibitor medications are a catalytic substance from liver and these enzymes are crucial for the metabolism of many drugs Cilostazol is being broken down by CMP and more of active metabolite = more side effects so lower dosage because it is an inhibitor Adverse effects ○ HA ○ Diarrhea ○ Palpitations ○ CHF has been reported w/ other PDE III inhibitors; contraindicated for use in patients w/ CHF If you vasdilate too much and because heart is being worked too much when it is already undergoing failure, exacerbates symptoms and contraindicated Drug interactions ○ Cilostazol could have pharmacokinetic interactions b/c of the effects of other drugs on its metabolism by CYP3A4 (eg, Erythromycin, Ketoconazole) or CYP2C19 (eg, Omeprazole) Contraindications ○ CHF of any severity (other oral phosphodiesterase inhibitors have been shown to increase mortality in patients w/ CHF) ○ ○ ADP receptor antagonists used more for heart issues (P2Y12 receptors) Clopidogrel (common)- Plavix MOA ○ Inhibit platelet aggregation by inhibiting ADP-induced platelet fibrinogen binding (this links platelets together to form aggregates or “plugs”) Clopidogrel and Prasugrel are irreversible inhibitors Blocking the receptors and because they are irreversible, too much platelets/substrate = action will not be overturned anyway. The only way it can stop is by reversing it. Ticagrelor is reversible Too much platelets/substrate = inhibition activity will occur by the drug DVT (Deep Vein Thrombosis) most common site of DVT occurs in the popliteal vein, behind the knee. Thrombosis breaks up in circulation and ends up pulmonary artery - does not cause a stroke Foramen ovale is the connection that is closed at birth ○ When it is not closed at birth, down syndrome have a patent foramen ovale, passes onto L atrium and DVT can cause a stroke ○ Antiplatelet effect takes 24-48 hours to develop; loading dose employed ○ Used in CVA, CVD, PVD, stent insertion Dosing ○ Loading doses are used to decrease the time to maximal platelet inhibition 75 mg PO QD takes 7 days for maximal effect 300 mg PO X1 before PCI takes 6-10 hrs for maximal effect Depends on age, vascular system, how their tolerant to medications Older, just use the 300 and as you go on you may increase the dosage ○ Want hypercoagulated state with PCI’s 600 mg PO x1 before PCI takes 2 hrs for maximal Maintenance dose ○ 75 mg PO QD  Adverse effects ○ Both can cause GI upset, diarrhea and rash Drug interactions ○ CYP2C19 inhibitors may decrease effectiveness because decreased conversion to an inactive metabolite Contraindications ○ Known hypersensitivity ○ Active pathological bleeding such as peptic ulcer or intracranial hemorrhage Prasugrel (Effient) (not used or talked about a lot) FDA indications ○ Reduces rate of thrombotic cardiovascular events (eg, stent thrombosis) in patients w/ unstable angina, non-ST-segment elevation MI, or ST-elevation MI (STEMI) managed w/ percutaneous coronary intervention (PCI) Dosing ○ Loading dose 60 mg ○ Maintenance dose 10 mg (in combination w/ aspirin 81-325 mg/day) Adverse effects similar to other ADP antagonist ○ Bleeding risks may be higher for certain patient populations (see warnings) Contraindications ○ Peptic ulcer disease ○ Intracranial hemorrhage ○ TIA/Stroke Ticagrelor (Brilinta)- far better medication than Plavix according to DJ FDA indications ○ ACS (w/ Aspirin)- reduces risk of CV death, MI, stroke, and stent thrombosis Dosing ○ Loading dose 180 mg ○ Maintenance dose 90 mg BID (in combination w/ aspirin 81mg/day) Do NOT use a higher of Aspirin as it reduces the effectiveness Drug interactions ○ Avoid w/ strong CYP 3A4 inhibitors Adverse effects ○ Bleeding The first time you see this on a patient, petechiae will appear due to a hypercoagulation state ○ Bradycardia, dyspnea, gynecomastia in men  Gynecomastia: enlargement or swelling of breast tissue in males, often caused by an imbalance between testosterone and estrogen levels Contraindications ○ Peptic ulcer disease ○ Intracranial hemorrhage ○ Severe hepatic impairment ○ GPIIb/IIIa receptor inhibitors Includes the agents Tirofiban (Aggrastat) and Eptifibatide (Integrilin) Antagonists of the platelet glycoprotein (GP) IIb/IIIa receptor - the major platelet surface receptor involved in platelet aggregation Platelets become activated, it releases ADP to activate nearby platelets to “grow arms”, hook and catch platelets ○ It forms like accumulation of platelets that are holding on together to come to this area of where the vessel injury is = platelet plug formation Potent antithrombotic effects and has been shown to decrease mortality and reinfarction Clinical use Indicated for use in acute coronary syndrome, including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI) Integrilin has the broadest indications ○ Elective, urgent or emergency PCI ○ Patients w/ UA/NSTEMI who are medically managed and those undergoing PCI Aggrastat is not used in elective, urgent or emergency PCI Dosing of Aggrastat Loading infusion rate (0.4 mg/kg/min for 30 min.) followed by maintenance infusion rate (0.1 mg/kg/min) Larger margin of safety than Reopro ○ Reversible platelet aggregation due to short ½ life (2 hrs) ○ Platelet function is restored toward baseline (< 50 % inhibition) w/in 4 hours after infusion Used in combination w/ aspirin and heparin  Dosing of Integrilin Bolus and constant infusion rate based on indication and patient characteristics such as weight, serum creatinine- see protocol Reversible following cessation of infusion (½ life = 2.5 hr) Adverse reactions (both): High incidence of bleeding Thrombocytopenia (less than w/ Reopro) Abciximab (common) (Reopro) MOA ○ Fab fragment of a human-murine monoclonal antibody (MAB) that binds to the platelet glycoprotein (GP) IIb/IIIa receptor leading to inhibition of platelet aggregation Clinical use ○ Used as an adjunct to percutaneous transluminal angioplasty (PCTA) for the prevention of acute cardiac ischemic complications in patients at high risk for abrupt closure of the treated coronary vessel ○ Patients with UA/NSTEMI not responding to medical therapy when PCI is planned within 24 hours ○ Abciximab use in patients with UA or NSTEMI not undergoing PCI shows no significant benefit (GUSTO trial) Dosing ○ Low margin of safety Long ½ life affects platelet function for 12-24 hrs after infusion No antidote for over-dose ○ Used w/ aspirin and heparin ○ Usual dose is 0.25 mg/kg via IV bolus given 10-60 min. before the start of PCl, followed by continuous infusion (10 mcg/min) for 12 hrs Adverse reactions ○ Bleeding ○ Formation of antibodies occurs in up to 6.5% of patients; percentage increases w/ repeated use ○ Anaphylaxis has NOT been reported ○ Severe thrombocytopenia occurs w/ repeat exposure Drug Interactions NSAIDs: increased risk for bleeding ○ Don’t use Ibuprofen + Aspirin in some cases Warfarin (anticoagulant ion medication that works on intrinsic factor in coagulation pathway; blocking factors w/ Vitamin K): gives additive effect which is an increased risk for bleeding Other antiplatelets: increased risk for bleeding