Anti Thrombolytics And Coagulants (Fc)

Front 1

Heparin MOA

Back 1

Accelerates antithrombin III activity (natural anticoagulant) binds thrombin & inactivates tissue factors

Antithrombin III also inactivates 9.10.11.12 (all a's) and kalikrien

Binds & interferes with platelet aggregation (high doses)

Others: Increase lipoprotein lipase activity & Inhibit smooth cell proliferation

Front 2

Clinical uses of Heparin

Back 2

Treatment: venous thrombosis, pulmonary embolism, early in unstable angina & acute MI
Prophylaxis, in surgery: prevent postoperative deep vein thrombosis & pulmonary embolism
Prophylaxis: clotting in blood transfusions, dialysis, blood samples, etc
DOC in pregnancy: does not cross placenta, so it is the anticoagulant used if pregnant

Front 3

Heparin kinetics

Back 3

Poor oral absorption  only IV or subQ forms (Immediate onset in IV; Short delay in subQ)

Metabolized by liver (depolymerization, desulfation);

Metabolites excreted by kidney
T1/2 depends on dose (non-linear)

Front 4

Monitoring parameters with heparin -

Back 4

APTT (activated partial thromboplastin time): coagulation monitoring, via measure of clotting time
Dose adjusted based on APTT measures
Monitor skin lesions (bleeding), thrombotic complications & UFH/platelets (HIT toxicity)

Front 5

Toxicity of Heparin -

Back 5

Bleeding: most common side effect, due to GPIIb/IIIa antagonism (platelet receptors); dose dependent bleeding

HIT or HAT

Liver toxicity (elevated LFTs), Osteoporosis (heparin binds osteoblasts, activating osteoclasts)

Front 6

HIT vs. HAT -

Back 6

Thrombocytopenia: heparin associated (HAT – benign; 2days) vs. heparin induced (HIT – serious; 1week)


HIT: autoimmune rxn to unfractionated heparin (UFH) ↓platelets, but get unwanted thrombotic events

Front 7

CI for Heparin use -

Back 7

Severe thrombocytopenia: major risk for bleeding

Front 8

Drug interactions for Heparin -

Back 8

↓effect: digoxin, tetracycline, nicotine, antihistamine

↑effect: anticoagulants, NSAIDs, ASA, dipyridamole, Plavix, direct thrombin inhibitors

Front 9

Antidote for heparin use -

Back 9

Antagonism, during overdose: Protamine sulfate tightly binds heparin & neutralizes it

Front 10

LMWH examples -

Back 10

Dalteparin, Enoxaparin, Tinzaparin

Front 11

Diff between Heparin and LMWH in terms of structure -

Back 11

Derived from standard heparin, depolymerized to approximately 1/3 size, 4000-5000 daltons

Front 12

MOA of LMWH -

Back 12

Smaller fragment than heparin, can only bind and inactivate factor Xa

Front 13

Uses of LMWH -

Back 13

(Similar to heparin); Special populations – end stage renal failure, obesity, pregnancy
Tx/Prophylaxis of DVT, PE; unstable angina & MI; orthopedic surgery; hemodialysis

Front 14

Kinetics of LMWH -

Back 14

SubQ injection
Not interchangeable between other anticoagulant agents  ie must continue with drug to continue effects
T1/2: reduced binding to macrophages & endothelial cells  increase in half life for once a day dosing

Front 15

Monitoring parameters with LMWH -

Back 15

Does not need monitoring: reduced nonspecific plasma protein binding -> predictable response (don’t need APTT)

Front 16

Advantages of LMWH -

Back 16

↓incidence HIT (↓binding to platelets)
↓incidence osteoporosis (↓binding to osteoblasts)

Front 17

Direct thrombin inhibitors examples -

Back 17

Hirudin
Lepirudin
Argatroban
Bivalirudin

Front 18

MOA of Direct thrombin inhibitors -

Back 18

Interacts directly with thrombin molecule (does not require antithrombin or heparin cofactor II)

Inhibits both circulating & clot-bound thrombin (potential advantage over heparins/LMWHs)

Front 19

Use of direct thrombin inhibitors -

Back 19

Alternative to heparin in patients with HIT (minimal cross reactivity to heparin induced antibodies)

Front 20

Toxicity of DTI -

Back 20

Bleeding: major bleeding incidence is high (15%)

Front 21

Char. of Hirudin

Back 21

Prototype, isolated from salivary secretions of medicinal leeches; All given IV

Front 22

Char of Lepirudin -

Back 22

Analog of Hirudin
IRREVERSIBLY binds thrombin
IV
Excreted through kidneys

Front 23

Char. of Argatroban -

Back 23

Synthetic molecule
Reversibly binds thrombin
IV
Liver metabolism

Front 24

Char. of Bivalirudin -

Back 24

Synthetic molecule
Reversibly binds thrombin
IV
Excreted through kidneys

Front 25

Direct Xa Inhibitor example -

Back 25

Fondaparinaux

Front 26

MOA of Direct Xa Inhibitor -

Back 26

Synthetic molecule
Reversible binds and accelerates Antithrombin III -> inhibition of factor Xa

Front 27

Use of Direct Xa inhibitor -

Back 27

Alternative to heparin in patients with HIT (minimal cross reactivity to heparin induced antibodies)

Front 28

Kinetics of Direct Xa Inhibitor -

Back 28

SubQ, with long half life (once a day dosing); Eliminated unchanged by kidney

Front 29

Warfarin (Coumadin) description -

Back 29

Racemic mixture of R, S isomers -> S is stronger (5x more potent)

Front 30

MOA of Warfarin -

Back 30

Interferes with hepatic synthesis of vitamin K dependent clotting factors (2, 7, 9, 10) and protein C, S
Interferes with synthesis of anticoagulants, protein C & S
Note: may see both bleeding or clotting as potential complications, since it blocks clotting factors & anticoagulants

Front 31

Clinical use of Warfarin -

Back 31

Prophylaxis/Treatment of venous thrombosis & pulmonary embolism

Cardiac diseases Atrial fibrillations with risk of embolism

Prosthetic heart valve & Rheumatic valve disease

(Start within 24 hours of Heparin; overlap of therapy, Heparin given while waiting for Warfarin)

Front 32

Kinetics of Warfarin -

Back 32

Oral (UNLIKE OTHER IV), good absorption

T1/2 of drug, 1-2 days; Liver metabolized and Urine/Feces excreted;

VERY HIGH PROTEIN BOUND (99%) - DRUG INTERACTIONS


Time to see full effect: months, since clotting factors have a very long T1/2 & it takes awhile to deplete them

Front 33

Food interactions with warfarin -

Back 33

Food high in vitamin K (leafy greens): must be consistent in diet; don’t binge on greens

Herbals increase the anticoagulant effects: Ginkgo, Ginger, Garlic, Vitamin E, St. John’s wart

Front 34

Antidote for Warfarin -

Back 34

fresh frozen plasma (replaces clotting factors)

Vit K

Front 35

Toxicity for Warfarin -

Back 35

Bleeding & Coumadin induced skin necrosis

Front 36

CI for Warfarin -

Back 36

Pregnancy (crosses placenta)
Uncontrolled bleeding & GI ulcers

Front 37

Monitoring parameters for Warfarin -

Back 37

PT: pro-time (bleeding time), expressed in INR (PTpatient/PTnormal)
International normalized ratio (INR)

Most therapeutic indications require INR to be ~2-3


As INR gets higher, more adverse effects are seen and at very high INR may need to give vitamin K & take off drug

Front 38

Medical prosthetic valves INR for Warfarin -

Back 38

2.5-3.5

everything else 2-3

Front 39

Aspirin MOA -

Back 39

Irreversibly inhibit cyclooxygenase (COX) -> prevents synthesis of Thromboxane A2
Thus, inhibits platelet aggregation & vasoconstriction

Front 40

Kinetics of Aspirin -

Back 40

Permanent action on platelet (irreversible), lasting for life of platelet (7-10 days)
Increased dose does not increase efficacy -> it just increases toxicity (bleeding)

Front 41

Dipyridamole MOA -

Back 41

Exact mechanism unknown; multiple things involved
Inhibit phosphodiesterase enzyme -> which degrades cAMP -> ↑cAMP in platelets, resulting in reduction of aggregation

Stimulates prostacyclin synthesis and potentiates the anti-platelet effects of prostacyclin

Front 42

Clinical uses of Dipyridamole

Back 42

Prevent embolization from prosthetic heart valves (given with Warfarin)

Reduce thrombosis in thrombotic disease (given with Aspirin)

Front 43

Ticlopidine MOA -

Back 43

Irreversibly inhibits platelet ADP receptor ->inhibits platelet aggregation

impairs activation of glycoprotein IIb/IIIa -> inhibit fibrinogen binding

Front 44

Kinetics Ticlopidine -

Back 44

Once a day dosing; Liver metabolism

Front 45

Toxicity Ticlopidine -

Back 45

Bleeding, GI problems

Severe neutropenia: must monitor CBC closely; therefore, drug not commonly used

Front 46

MOA of Clopidogrel (Plavix)

Back 46

Irreversibly inhibits platelet ADP receptor
impairs activation of glycoprotein IIb/IIIa
prevents aggregation

Front 47

Kinetics of Clopidogrel

Back 47

Twice a day dosing; Liver metabolism

Front 48

S/e of Clopidogrel

Back 48

Well tolerated (Clean version of Ticlopidine)

Front 49

Glycoprotein IIb/IIIa receptor antagonists examples -

Back 49

Eptifibatide, Tirofiban, Abciximab

Front 50

Mechanism of Glycoprotein IIb/IIIa receptor antagonists

Back 50

Monoclonal antibodies that binds to glycoprotein receptor IIb/IIIa on activated platelets and thus prevent aggregation

Front 51

Use of Glycoprotein IIb/IIIa antagonists

Back 51

Acute coronary syndrome at high risk for further MI; Ischemia

Front 52

Toxicity of Glycoprotein IIb/IIIa antagonists

Back 52

Bleeding & Thrombocytopenia (much less than Heparin)

Front 53

Examples of thrombolytics -

Back 53

Streptokinase, Urokinase, Alteplase, Anistreplase, Reteplase

Front 54

MOA of thrombolytics -

Back 54

Converts plasminogen to plasmin (all are tPA, except Streptokinase)  digestion of fibrin

Front 55

Clinical use of thrombolytics -

Back 55

Dissolve the formed clot (This and direct thrombin inhibitors do this)

Front 56

CI of thrombolytics -

Back 56

Bleeding risks: surgery within past 10 days; serious GI bleed within past 3 months; active bleeding disorder
Cardiac: aortic dissection, acute pericarditis
Previous stroke or other active intracranial problem

Front 57

Prasugrel MOA

Back 57

Blocked the platelet ADP receptor irreversibly
Similar to clopidogrel in effectiveness

Front 58

Kinetic of Prasugrel -

Back 58

Well absorbed and high protein bounded
T1/2 - 7 hrs
Prodrug - metabolized in liver by CYP3A4 and CYP 2B6 to be an active drug

Front 59

Adverse reactions and dosage of Prasugrel -

Back 59

black box warning - life threatening bleeding risk 1.3% pts

60 mg loading dose, 10mg MD

Use 5mg for <60kg

Front 60

nL number of platelets -
Function of platelets measured by -
Platelets derived from -
nL lifespan in blood -

Back 60

150k-450k/mm3 of blood
template bleeding time
megakaryocytes
10d

Front 61

Vascular injury wall -

Back 61

Injury causes the exposure of subendothelial extracellular colalgen

Arteriolar constriction -> due to reflex neurogenic mechanism and also because of local release of endothelin

Front 62

Adhesion step in platelet plug -

Back 62

vWF binds exposed collagen fibers in BM

Platelets adhere to vWF via glycoprotein Ib and become activated (shape change, degranulation and synth of TxA2)

Front 63

Deficiency of vWF -

Back 63

von Willebrand dz

Adom defect in quantity or quality of vWF-> leads to increase in bleeding time and increased PTT (as vWF stabilizes Factor VIII)

Front 64

Deficiency of glycoprotein Ib receptor -

Back 64

Bernard Soulier disease

defective platelet plug formation
impaired platelet to platelet aggregation

Front 65

Release contents of platelet dense bodies -

Back 65

ADP
Ca2+
Epinephrine
Histamine
Serotonin

Front 66

Release contents from platelet alpha granules -

Back 66

Fibrinogen
Fibronectin
Factor V
vWF
PDGF

Front 67

Aggregation step of platelet plug -

Back 67

ADP and TxA2 released by platelets and promote aggregation

Cross-linking of platelets by fibrinogen with help of GpIIb/IIIA receptor

Decreased endothelial secretion of anti thrombogenic substances ->( prostacyclin, NO, tPA, thrombomodulin)

Front 68

Glanzmann thrombasthenia -

Back 68

Defective platelet plug
Decreased GpIIb/IIIa receptor -> impaired platelet to platelet aggregation