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D&T - E1 > Anticoagulant, Antiplatelet, and Thrombolytic Agents > Flashcards

Anticoagulant, Antiplatelet, and Thrombolytic Agents Flashcards

1
Q

Anticoagulants

A

Prevent blood clotting

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2
Q

Antiplatelet

A

Inhibit platelet function

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3
Q

Thrombolytics

A

Dissolve formed clots

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4
Q

Anticoagulants include

A
  • Heparin
  • Enoxaparin, Dalteparin, Tinzeparin = LMW Heparins
  • Warfarin
  • Argatroban
  • Dabigatran
  • Fondaparinux
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5
Q

Antiplatelets include

A
  • Aspirin
  • Dipyridamole
  • Clopidogrel
  • Ticlopidine
  • Abciximab
  • Eptifibatide
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6
Q

Thrombolytics include

A
  • Streptokinase
  • Anisteplase
  • Tenecteplase
  • Alteplase
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7
Q

Heparin - Molecule

A
  • 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
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8
Q

Heparin - Mechanism of action

A
  • 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
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9
Q

Heparin - Therapeutic use

A
  • 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)
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10
Q

Heparin - Monitoring

A
  • ACTIVATED PARTIAL THROMBOPLASTIN TIME (aTPP), MONITORS COMMON AND INTRINSIC PATHWAY antithrombin III has poor activity against coagulation factor VII (PT time, extrinsic pathway)
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11
Q

Heparin - Adverse effects

A

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

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12
Q

Heparin - Treatment of excess hemorrhage

A
  • Administer plasma or blood containing coagulation factors

- PROTAMINE SULFATE: heparin-protamine complex cannot bind to AT-III

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13
Q

Heparin - Contraindications

A
  • Bleeding disorder

- Pre-existing bleeding sites

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14
Q

Enoxaparin, Dalteparin, and Tinzaprin - Molecule

A
  • Low molecular weight heparin fractionated from heparin MW 1000 - 10,000 daltons
  • Mean 4,500 daltons
  • Mean 15 monosaccharide units
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15
Q

Enoxaparin, Dalteparin, and Tinzaparin - Mechanism of action

A
  • Higher specificity for enhanced antithrombin III inactivation of Xa
  • > 5400 kDa or 18 monosaccharide units required to bind simultaneously AT-III and thrombin
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16
Q

Enoxaparin, Dalteparin, and Tinzaparin - Therapeutic use

A
  • 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)
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17
Q

Enoxaparin, Dalteparin, and Tinzaparin - Condraindications and Adverse effects

A
  • Bleeding

- Contraindicated in presence of bleeding disorder or active bleeding site

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18
Q

Enoxaprin, Dalteparin, and Tinzaparin - Current perception of advantages for unfractionated heparin

A
  • 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
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19
Q

Fondaparinux - Mechanism of action

A

Synthetic pentasaccharide binds to ATII to accelerate only factor Xa inactivation

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20
Q

Fondaparinux - Therapeutic use

A
  • 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)
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21
Q

Fondaparinux - Adverse effects

A

Bleeding

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22
Q

Fondaparinux - Contraindications

A
  • Active bleeding

- SEVERE RENAL IMPAIRMENT (

23
Q

Warfarin - Mechanism of action

A
  • 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)
24
Q

Warfarin - Therapeutic use

A
  • 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
25
Q

Warfarin - Monitoring

A

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

26
Q

Warfarin - Adverse effects and Contraindications

A
  • 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
27
Q

Warfarin - Treatment of overdose

A
  • Whole blood or plasma

- Vitamin K1 (phytonadione)

28
Q

Argatroban and Dabigatran etexilate - Mechanism of action

A
  • Both are DIRECT THROMBIN INHIBITORS, block active site of thrombin
  • Active on free and fibrin bound thrombin (action independent of ATIII)
29
Q

Argatroban

A
  • IV administration
  • Treatment and prophylaxis in thrombosis with heparin induced thrombocytopenia
  • Monitor with aPTT
30
Q

Dabigatran

A
  • 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
31
Q

Argatroban and Dabigatran - Side effects

A
  • Bleeding

- NO AVAILABLE ANTIDOTE

32
Q

Antiplatelet drugs - Background

A

The goal of therapy is to diminish platelet function. These drugs are used primarily in arterial thrombotic disease such as

  1. Transient ischemic attacks
  2. Unstable angina
  3. History of myocardial infarction
33
Q

Aspirin - Mechanism of action

A
  • Inhibits platelet aggregation
  • Irreversible inhibitor of COX (acetylates the enzyme)
  • Platelet prostaglandin formation (TXA2) inhibited
  • BLOCKS SYNTHESIS OF PGG2 FROM ARACHIDONIC ACID
34
Q

Aspirin - Adverse effects

A
  • GI bleeding, pain and peptic ulcers

- Bleeding

35
Q

Dipyrimadole - Mechanism of action

A

Inhibits phosphodiesterase, ↑ platelet cAMP

36
Q

Dipyrimadole - Therapeutic use

A
  • Use with other agents, very little benefit if given alone

- Given with warfarin for prevention of thromboembolism in patients with prosthetic heart valves

37
Q

Clopidogrel, Ticlopidine, and Cangelor - Mechanism of action

A
  • 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
38
Q

Clopidogrel, Ticlopidine, and Cangrelor - Therapeutic use

A

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
39
Q

Clopidogrel, Ticlopidine, and Cangrelor - Adverse effects

A
  • Bleeding due to diminished platelet function
  • Thrombocytopenia purpura (higher risk with ticlopidine)
  • Ticlopidine can cause life threatening agranulocytosis
  • Must monitor WBC and platelets
40
Q

Abciximab and Eptifibatide - Mechanism of action

A
  • Platelet glycoprotein IIIa/IIb receptor antagonists
  • Competitive reversible inhibitor
  • Inhibit platelet crosslinking with fibrinogen
  • Monoclonal antibody Fab fragment
41
Q

Abciximab and Eptifibatide - Therapeutic use

A
  • Acute coronary syndrome (unstable angina)
  • Prevent acute ADJUNCT with angioplasty
  • Administered IV (bolus plus infusion)
42
Q

Abciximab and Eptifibatide - Adverse effects

A
  • Bleeding

- Increased bruising

43
Q

Abciximab and Eptifibatide - Contraindications

A
  • 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
44
Q

Fibrinolytic and Anti-Fibrinolytic Agents - Background

A
  • 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
45
Q

Streptokinase - Molecule

A

Protein derived from beta-hemolytic streptococci; antigenic

46
Q

Streptokinase - Mechanism of action

A
  • 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
47
Q

Streptokinase - Therapeutic use

A
  • Reperfusion of occluded coronaries following acute MI
  • Pulmonary embolism
  • Arterial thrombosis
48
Q

Streptokinase - Adverse effects

A
  • 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)
49
Q

Streptokinase - Contraindications

A
  • Surgery or trauma in past 10 days
  • Preexisting bleeding disorder or episode
  • Intracranial trauma
  • DIASTOLIC BP > 110
50
Q

Antistreplase

A
  • 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
51
Q

Alteplase, Reteplase, rt-PA - Mechanism of action

A
  • Activates fibrin bound plasminogen more selectively than circulating plasminogen
  • Lytic state is less marked than observed with streptokinase
52
Q

Alteplase, Reteplase, rt-PA - Therapeutic use

A
  • Reperfusion of cornonary arteries in acute MI
  • PE
  • Thrombotic stroke
53
Q

Tenecteplase

A
  • Genetically engineered derivative of alteplase
  • Tenecteplase longer half-life greater fibrin specificity than alteplase and slower inactivation by PAI-1
  • Approved for MI
54
Q

Aminocaproic acid

A
  • Inhibitor of plasminogen activation

- Lysine analog, compete for lysine binding site on plasminogen and plasmin

D&T - E1 (11 decks)

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