Anticoagulant, Antiplatelet, and Thrombolytic Agents Flashcards
Anticoagulants
Prevent blood clotting
Antiplatelet
Inhibit platelet function
Thrombolytics
Dissolve formed clots
Anticoagulants include
- Heparin
- Enoxaparin, Dalteparin, Tinzeparin = LMW Heparins
- Warfarin
- Argatroban
- Dabigatran
- Fondaparinux
Antiplatelets include
- Aspirin
- Dipyridamole
- Clopidogrel
- Ticlopidine
- Abciximab
- Eptifibatide
Thrombolytics include
- Streptokinase
- Anisteplase
- Tenecteplase
- Alteplase
Heparin - Molecule
- Unfractionated contains molecules with MW 15,000-30,000 daltons
- Mean 12,000 daltons
- Mean 40 monosaccharide units
- Fractionation due to action of ENDO-D-GLUCORONIDASE
Heparin - Mechanism of action
- Accelerations (1000 fold) inactivation by antithrombin III (AT-III) of intrinsic and common pathways including: THROMBIN (II), IXa, Xa
- Thrombin, IXa, Xa BIND IRREVERSIBLY to ARG-SER site on AT-III
- Heparin binding to AT-III is REVERSIBLE; heparin binding site is specific pentasaccharide sequence that contains a 3-O-SULFATED GLUCOSAMINE residue which recognizes AT-III require minimum of 18 monosaccharide unites to bind AT-III and thrombin
Heparin - Therapeutic use
- ANTICOAGULANT ACTIVITY IN VIVO (when injected into body)
- ANTICOAGULANT ACTIVITY IN VITRO (when added to blood in test tube)
- Venous thrombosis
- Pulmonary embolism
- Patency of IV canals
- ANTICOAGULANT IN PREGNANCE (discontinue 25 hours prior to induction of labor)
- Administer by injection (large polar molecule, not absorbed oral): immediate effects if given IV; onset delayed onset (1-2 hours) with subcutaneous ; INTRAMUSCULAR CONTRAINDICATED (induces painful hematoma)
- Other effect - LIPID CLEARING EFFECT HEPARIN ACTIVATES LIPOPROTEIN LIPASE (cleave TG from VLDL)
Heparin - Monitoring
- ACTIVATED PARTIAL THROMBOPLASTIN TIME (aTPP), MONITORS COMMON AND INTRINSIC PATHWAY antithrombin III has poor activity against coagulation factor VII (PT time, extrinsic pathway)
Heparin - Adverse effects
Bleeding:
- THROMBOCYTOPENIA type I (HIT-I): nonimmune occurs within 2 days of initiating therapy; mediated by platelet heparin interaction
- Type II (HIT-II): immune mediated, more severe. Heparin therapy needed for 5-10 days. Antibodies form against the HEPARIN-PLATELET FACTOR 4 COMPLEX and bind on platelet surface causing aggregation
Osteoporosis if given for more than 6 months
Heparin - Treatment of excess hemorrhage
- Administer plasma or blood containing coagulation factors
- PROTAMINE SULFATE: heparin-protamine complex cannot bind to AT-III
Heparin - Contraindications
- Bleeding disorder
- Pre-existing bleeding sites
Enoxaparin, Dalteparin, and Tinzaprin - Molecule
- Low molecular weight heparin fractionated from heparin MW 1000 - 10,000 daltons
- Mean 4,500 daltons
- Mean 15 monosaccharide units
Enoxaparin, Dalteparin, and Tinzaparin - Mechanism of action
- Higher specificity for enhanced antithrombin III inactivation of Xa
- > 5400 kDa or 18 monosaccharide units required to bind simultaneously AT-III and thrombin
Enoxaparin, Dalteparin, and Tinzaparin - Therapeutic use
- Prophylaxis and acute DVT, PE, orthopedic, and abdominal surgery
- Unstable angina or non-Q-wave MI
- Administer subcutaneous
- Monitor anti-Xa activity
- ANTICOAGULANT IN PREGNANT WOMEN (discontinue 25 hours prior to induction of labor)
Enoxaparin, Dalteparin, and Tinzaparin - Condraindications and Adverse effects
- Bleeding
- Contraindicated in presence of bleeding disorder or active bleeding site
Enoxaprin, Dalteparin, and Tinzaparin - Current perception of advantages for unfractionated heparin
- Longer interval between doses (outpatient, 1x per day dosing)
- Slight increase or no change in activated aPTT
- Does not require monitoring; could monitor anti-Xa activity
- Better predictability of response to a give dose
- Less thrombocytopenia, reduced binding to platelets
Fondaparinux - Mechanism of action
Synthetic pentasaccharide binds to ATII to accelerate only factor Xa inactivation
Fondaparinux - Therapeutic use
- IV, SC administration
- DVT acute and postoperative (hip and knee replacement)
- PE
- Can be used in pregnancy (discontinue 24 hours prior to induction of labor)
Fondaparinux - Adverse effects
Bleeding
Fondaparinux - Contraindications
- Active bleeding
- SEVERE RENAL IMPAIRMENT (
Warfarin - Mechanism of action
- Inhibits hepatic synthesis of biologically active vitamin K dependent clotting factors, PROTEIN C AND S
- Biological activity requires GAMMA-CARBOXYGLUTAMYL RESIDUES on clotting factors; 2 carboxyl groups necessary for chelation of calcium and binding to platelet phospholipids
- Warfarin inhibits conversion of Vitamin K epoxide to hydroquinone (reduced vitamin K that can act as a cofactor)
Warfarin - Therapeutic use
- DRUG OF CHOICE FOR ORAL ANTICOAGULANT
- Prophylaxis to prevent venous thromboembolism and pulmonary embolism
- Used in individuals with PROSTHETIC HEART VALVES
- Arterial thromboembolism prophylaxis in atrial fibrillation
- DELAYED THERAPEUTIC EFFECT, INITIAL EFFECT OCCURS IN 24 HOURS AND MAXIMAL EFFECT TAKES 5-7 DAYS
- WARFARIN IS EFFECTIVE AS AN ANTICOAGULANT ONLY WHEN ADMINISTERED IN VIVO
Warfarin - Monitoring
INR laboratory standardized quick one-stage PT
- Citrate plasma incubated with tissue thromboplastin and calcium
- MONITOR EXTRINSIC PATHWAY WITH PROTHROMBIN TIME (PT)
Difference in thromboplastin source and/or lots cause inter and intra laboratory variability
- INR (international normalized ratio) standardizes reagent thromboplastin to an International Reference Preparation (IRP) of thromboplastin
- ISI international sensitivity index is the correction factor to compare commercial thromboplastin to the first brain thromboplastin (IRP) values for ISI are 1-2.4
Goal for INR is 2.0 - 3.0; prophylactic for heart valve INR is 2.5 - 3.0
INR = (patient PT/ mean normal PT)^ISI
Warfarin - Adverse effects and Contraindications
- HEMORRHAGE
- ADVERSE REACTIONS MORE LIKELY TO OCCUR IF: changes occur in absorption or metabolism of warfarin or vitamin K; alterations occur in synthesis or catabolism of coagulation factors; change in fibrin degradation; change in platelet function or number
- GENETIC PREDISPOSITION: genetic variants of CYP2C9 and VKORC1 genes use less warfarin
- Numerous drug-drug interactions due to binding displacement (1% free fraction) and warfarin metabolism mediated by cytochrome P450
- Contraindicated in patients with bleeding disorder or existing bleeding site
- Contraindicated in pregnant women (congenital abnormalities occur if fetus is exposed; greater incidence of neonatal and fetal hemorrhage
Warfarin - Treatment of overdose
- Whole blood or plasma
- Vitamin K1 (phytonadione)
Argatroban and Dabigatran etexilate - Mechanism of action
- Both are DIRECT THROMBIN INHIBITORS, block active site of thrombin
- Active on free and fibrin bound thrombin (action independent of ATIII)
Argatroban
- IV administration
- Treatment and prophylaxis in thrombosis with heparin induced thrombocytopenia
- Monitor with aPTT
Dabigatran
- Oral administration
- Prodrug converted by esterase’s to Dabigatran (active)
- Converted to 4 different GLUCURONIDES (active)
- NOT A P450 SUBSTRATE
- Substrate for P-glycoprotein transport, drug interactions RIFAMPIN induces P-glycoprotein decrease dabigatran blood levels
- Venous thrombosis prophylaxis
- Prevent stroke with ATRIAL FIBRILLATION
- Use with caution in diminished RENAL EXCRETION
Argatroban and Dabigatran - Side effects
- Bleeding
- NO AVAILABLE ANTIDOTE
Antiplatelet drugs - Background
The goal of therapy is to diminish platelet function. These drugs are used primarily in arterial thrombotic disease such as
- Transient ischemic attacks
- Unstable angina
- History of myocardial infarction
Aspirin - Mechanism of action
- Inhibits platelet aggregation
- Irreversible inhibitor of COX (acetylates the enzyme)
- Platelet prostaglandin formation (TXA2) inhibited
- BLOCKS SYNTHESIS OF PGG2 FROM ARACHIDONIC ACID
Aspirin - Adverse effects
- GI bleeding, pain and peptic ulcers
- Bleeding
Dipyrimadole - Mechanism of action
Inhibits phosphodiesterase, ↑ platelet cAMP
Dipyrimadole - Therapeutic use
- Use with other agents, very little benefit if given alone
- Given with warfarin for prevention of thromboembolism in patients with prosthetic heart valves
Clopidogrel, Ticlopidine, and Cangelor - Mechanism of action
- Ticlopidine and Clopidogrel block ADP binding at purinergic P2Y12 receptor. ADP release stimulates platelet purinergic receptrs P2Y1 and P2Y12. P2Y1 activation causes TXA2 release, increasing PI hydrolysis and a rise in intracellular Ca. P2Y12 activation inhibits cAMP formation. A full response to ADP requires activity of both P2Y1 and P2Y12 receptors. Inhibition of either P2Y1 or P2Y12 receptors is sufficient to impair ADP action on platelets
- Ticlopidine and Clopidogrel are prodrugs
- Clopidogrel metabolite and Ticlopidine thiol metabolite are IRREVERSIBLE INHIBITORS of PY12 receptor. Ticlopidine metabolite forms a disulfide bridge between the drug and a CYS residue on the receptor.
- CANGRELOR IS A REVERSIBLE INHIBITOR, IV ADMINISTRATION
Clopidogrel, Ticlopidine, and Cangrelor - Therapeutic use
Both:
- Reduce the risk of thrombotic events in predisposed individuals
- CLOPIDOGREL PREFERRED, better safety profile and shorter duration of action
- Ticlopidine peak action takes 5 days and residual action last 72 hours after treatment. Normal platelet function returns when drug is stopped after new platelets are made
Ticlopidine:
- Reduce thrombotic events following a stroke
- Second line due to side effects, USED IF RESPONSE FAILS WITH ASPIRIN
Clopidogrel:
- Reduce thrombotic events following MI, stroke, unstable angina or peripheral arterial disease
Cangrelor:
- IV administration
- Quickly reversible
Clopidogrel, Ticlopidine, and Cangrelor - Adverse effects
- Bleeding due to diminished platelet function
- Thrombocytopenia purpura (higher risk with ticlopidine)
- Ticlopidine can cause life threatening agranulocytosis
- Must monitor WBC and platelets
Abciximab and Eptifibatide - Mechanism of action
- Platelet glycoprotein IIIa/IIb receptor antagonists
- Competitive reversible inhibitor
- Inhibit platelet crosslinking with fibrinogen
- Monoclonal antibody Fab fragment
Abciximab and Eptifibatide - Therapeutic use
- Acute coronary syndrome (unstable angina)
- Prevent acute ADJUNCT with angioplasty
- Administered IV (bolus plus infusion)
Abciximab and Eptifibatide - Adverse effects
- Bleeding
- Increased bruising
Abciximab and Eptifibatide - Contraindications
- History of hemorrhagic stroke
- Active internal bleeding or GI/genitourinary bleeding in past 6 weeks
- Thrombocytopenia
- Major surgery or trauma in past 6 weeks
- CANNOT USE CONCURRENT WITH WARFARIN
Fibrinolytic and Anti-Fibrinolytic Agents - Background
- Fibrinolytic system restricts clot expansion and degrades fibrin during wound healing
- Plasmin is a nonspecific protease that degrades fibrin, fibrinogen and other clotting factors
- Plasmin action on fibrinogen yields fibrinogen degradation products (FDP) which inhibit further conversion of fibrinogen to fibrin
- Plasminogen and plasmin bind fibrin at a LYSINE rich binding side
- t-PA is released from endothelial cells at a site of injury, tPA binds to fibrin via LYSINE binding sites at the amino terminus and activates bound plasminogen 300x faster than it activates circulating plasminogen
- IDEAL THROMBOLYTIC DRUG WOULD DEGRADE ONLY DESIDRED THROMBI AND NOT OLD FIBRIN DEPOSITS
NATURAL REGULATION OF FIBRINOLYSIS
- Damage releases tPA from endothelium
- tPA inactivated by circulating plasminogen activator inhibitor -1 (PAI-1)
- Alpha2-antiplasmin binds covalently to plasmin at a lysine rich binding site causing inactivation; OCCURS ONLY WITH CIRCULATING PLASMIN
- LYTIC STATE: circulating plasmin > capacity of alpha2 - antiplasmin
Streptokinase - Molecule
Protein derived from beta-hemolytic streptococci; antigenic
Streptokinase - Mechanism of action
- Complexes stoichiometrically 1:1 with plasminogen
- Conformational change of plasminogen exposes catalytic site for conversion of a second plasminogen to plasmin
- Acts on fibrin bound and circulating plasminogen; lytic state may occur
- Lytic state: circulating plasmin > capacity alpha2-antiplasmin
Streptokinase - Therapeutic use
- Reperfusion of occluded coronaries following acute MI
- Pulmonary embolism
- Arterial thrombosis
Streptokinase - Adverse effects
- HIGH ANTIGENIC ACTIVITY; FEVER
- BLEEDING (lysis of fibrin at sites of vascular injury; systemic lysis of fibrin, fibrinogen and clotting factors; provide plasma to replenish clotting factors and fibrin)
Streptokinase - Contraindications
- Surgery or trauma in past 10 days
- Preexisting bleeding disorder or episode
- Intracranial trauma
- DIASTOLIC BP > 110
Antistreplase
- Streptokinase complexed with human lys-plasminogen. The active catalytic center is blocked by an acyl group.
- Designed to provide more specific binding to thrombi
- Acyl group removed by plasma enzymes
- Similar uses and side effects to streptokinase
Alteplase, Reteplase, rt-PA - Mechanism of action
- Activates fibrin bound plasminogen more selectively than circulating plasminogen
- Lytic state is less marked than observed with streptokinase
Alteplase, Reteplase, rt-PA - Therapeutic use
- Reperfusion of cornonary arteries in acute MI
- PE
- Thrombotic stroke
Tenecteplase
- Genetically engineered derivative of alteplase
- Tenecteplase longer half-life greater fibrin specificity than alteplase and slower inactivation by PAI-1
- Approved for MI
Aminocaproic acid
- Inhibitor of plasminogen activation
- Lysine analog, compete for lysine binding site on plasminogen and plasmin
