Charmanticoagulant,antiplatelet,thrombolytics

Front 1

What five things are needed for each step of the coagulant pathway?

Back 1

1) A protease from the preceding stage
2) Zymogen
3) Nonenzymatic cofactor
4) Ca
5) Surface (usually platelets)

Front 2

Extrinsic Pathway vs. Intrinsic pathway

Back 2

In vivo TF activates VII to VIIa which activates X to Xa which converts II to IIa which converts Fibrinogen to Fibrin and activates XIII to XIII to crosslink Fibrin. The intrinsic pathway acts via XII, XI, IX and VIII + PL to activate X

Front 3

Protein C and S
What is their function and how are they activated?

Back 3

To prevent clotting in the vicinity of normal endothelium. Protein C is activated by plasminogen only in the presence of thrombomodulin release from intact endothelial cells. Protein C with Protein S and Ca then inactivate II(Thrombin) and X

Front 4

PGI2 role in homeostasis?

Back 4

Inhibits platelet aggregation

Front 5

Antithrombin action?

Back 5

Inhibits factors of intrinsic and common coagulation pathways.

Front 6

List the Vit K dependent factors involved in coagulation pathway and why Vit K is needed.

Back 6

II, VII, IX, X, Protein C, Protein S need Vit K to cause a conformational change to create a binding spot for Ca.

Front 7

Unfractionated Heparin
1) Drug class
2) Mechanism of action
3) Adverse effect

Back 7

1) Anticoagulant
2) Potentiates actions of Antithrombin to inhibit Thrombin and Xa. To inhibit thrombin both thrombin and antithrombin must bind to UFH --> cannot act in clot because it is too big. To inhibit Xa only antithrombin must bind to UFH.
3) Also inhibits platelet aggregation which can lead to undesired bleeding.

Front 8

Low Molecular Weight Heparin
1) Drug class
2) Mechanism of action
3) Adverse effect?

Back 8

1) Anticoagulant
2) Potentiates actions of antithrombin to inhibit Xa and thrombin. LMWH is less able to bind both antithrombin and thrombin so its most important role is in inhibiting Xa, for which only antithrombin must bind LMWH.
3) Does not inhibit platelet aggregation so does not cause bleeding.

Front 9

UFH
1) Administration and why?
2) Dosing effects?
3) Metabolism
4) Maternal --> fetus/baby exchange?

Back 9

1) Subcutaneous or intravenous b/c has huge first pass metabolism.
2) Very difficult to predict b/c drug binds to plasma proteins, endothelial cells and macrophages decreasing its bioavailability. Bioavailability also differs between subcutaneous and IV admin.
3) 50% met by macrophages, endothelial cells and liver. 50% excreted unchanged in kidney. t1/2 e is dose dependent, as Macrophages and endothelial cells fill up t 1/2 gets longer b/c most get metabolized in kidney
4) No exchange UFH is too big

Front 10

UFH Adverse effects:

Back 10

-Bleeding, antidote --> protamine sulfate
-Diminishing platelet levels to less than 50% --> discontinuation of drug. Mediated by IgG complex to Platelet Factor4-heparin --> paradoxical thrombosis.
-loss of hair
-hypersensitivity reactions
-natriuresis and slight hyperkalemia

Front 11

LMWH and Foundaparinux compared with UFH
1) Administration
2) Bioavailability
3) t1/2
4) Adverse effects

Back 11

1) SC or IV
2) Better than UFH b/c binds less to plasma proteins, endothelial cells, and macrophages.
3) longer b/c only eliminated by kidney
4) Less bleeding, but unfortunately too small for protamine sulfate to be effective.

Front 12

Uses of LMWH?

Back 12

Venous thrombosis
PE
ACS
Thrombolysis in MI
Percutaneous coronary intervention
Moderate-high risk surgery
Hip/knee replacement
surgery
major trauma with VTE risk factors
Hospitalized pts with CHF
Bridging therapy for warfarin requirements
Airplane travelers with VTE risk

Front 13

Warfarin/Coumadin
1) Drug class
2) Mechanism of action
3) Administration
4) Time to action?
5) Maternal issues

Back 13

1) Anticoagulant, oral
2) Inhibits Vit K reductase making reduced K unavailable to II, VII, IX, and X.
3) Oral
4) Peak plasma conc in 2-8 hrs but not active until previously activated factors decline 6-60 hr half lifes)
5) Cross placenta and can cause bleeding and intrauterine death, also crosses into breast milk

Front 14

Coumadin/Warfarin
Adverse effects

Back 14

1) Bleeding: can be counteracted by Vit K administration but Vit K takes a while to work so for severe bleeds must infuse blood with active coag factors.
2) Skin necrosis due to widespread microthrombosis of vasculature due to inhibition of Protein C and Protein S

Front 15

DDI
1) Increased Warfarin Response
2) Decreased Warfarin Response

Back 15

1) a) Lack of Vit K from dietary deficiency, antibiotics (decreased absorption from GI), in biliary or small bowel disease.
b) Decreased synthesis of II, VII, IX and X due to liver disease, Cong HF, Age
c) Increased degradation of same factors from fever, hyperthyroidism

Front 16

DDI
2) Decreased Warfarin Response

Back 16

2) a) increased dietary Vit K
b) Increased synthesis of factors due to pregnancy
c) Decreased degradation of factors, hypothyroidism
d) Increased warfarin clearance
e) Genetic warfarin resistance

Front 17

Coumadin DDI
1) Additive drugs
2) Decreased anticoagulant response

Back 17

1) a) Additive anticoag: Aspirin, decreased Vit K synthesis (kanamycin, tetracycline), decreased K absorption (laxatives)
b) Met inhibition: cimetidine, phenylbutazon, chloral hydrate
c) Displacement of warfarin from albumin: clofibrate
d) Increased GI tract ulceration
2) Stimulation of warf met: barbituates, rifampin, alcohol excess
Increased GI elim: cholestyramine.

Front 18

Bivalrudin
1) Drug class
2) Mechanism of action
3) Advantage over heparin?
4) Clinical uses
5) Adverse effects

Back 18

1) Anticoagulant
2) Anti thrombin. Also antiplatelet aggregation.
3) Smaller so can act on thrombin in clot and may act to lyse clot
4) To prevent clot during hip surgery, post percutaneous tranluminal angioplasty, MI in UA, adjunct to thrombolytic drugs, prevent strokes in a fib patients, anticoag in heparin induced thrombocytopenia.
5) Bleeding (no antidote, fresh blood must be give), allergic rx, no

Front 19

For which type of thrombi are anticoagulant drugs not sufficient and why? For which types of thrombi are they effective?

Back 19

Anticoagulants are not very effective in txt of arterial thrombi due to the active role of platelets in clot formation. They are effective in venous thrombosis where the platelets play much less of a role.

Front 20

Which diseases/processes are common to:
a) arterial thrombi
b) venous thrombi

Back 20

1) MI, Atrial fibrillation, stroke, rheumatic heart disease, valvular heart disease, valvular prosthesis, vascular insufficiency in lower extremities/bowel, and myocardial or aortic aneurysms.
b) congestive heart failure, cancer, pregnancy, surgical procedures, immobilization and trauma, and can lead to pulmonary embolism.

Front 21

Which approach is taken in txt of arterial thrombi?

Back 21

Antiplatelet due to extensive role they play in clot formation.

Front 22

Aspirin
1) Drug class
2) Mechanism of action
3) Administration
4) Adverse effects

Back 22

1) Antiplatelet
2) Inhibits COX irreversible in platelets and reversible in endothelial cells --> decrease in TXA which --I platelet aggregation and vasospasm. However it also inhibits prostacyclin formation in endothelial cells which vasodilates and inhibits platelet aggregation.
4) Low dose is used b/c this is found to inhibit COX in platelets more than endothelial cells --> less prostacyclin inhibition. Plus admin every other day allow endothelial cells to recover while platelet's COX is irreversible inhibited.
4) -Excess bleeding
-Hypersensitivity
-Aspirin-exacerbated respiratory tract disease
-Aspiring-induced uticaria

Front 23

Aspirin: Clinical uses

Back 23

Ischemic Heart Disease:
a) UA: TXA effects inhibits transient platelet agg and vasospasm in atherosclerotic regions
b) Acute MI: prophylactic therapy for pts with Hx of MI or no Hx
c) coronary artery bypass grafts: helps keep grafted arteries open that often close by end of first year.
d) Coronary angioplasty: reduces reoclusion
e) TIA: prolongs stroke free survival time.

Front 24

Dipyridamole
1) Drug class
2) Mechanism of action
3) Use

Back 24

1) Antiplatelet, vasodilator
2) Inhibits adenosine uptake by red cells -->greater plasma adenosine --> vasodilation. Adenosine is released by hypoxic myocardial cells. Also weak phosphodiesterase inhibitor --> increased cAMP levels in platelet --> inhibition of platelet aggregation.
3) When aspirin is not tolerated and as adjunct with aspirin for patients with first TIA.

Front 25

abciximab
1) Drug class
2) Mechanism of action
3) Administration
4) T1/2
5) Clinical uses
6) Adverse effects

Back 25

Rheopro
1) Antiplatelet
2) Fab fragment binds GPIIa/IIIb receptor in platelet and inhibits platelet aggregation via fibrinogen and vWF
3) IV bolus only
4) High affinity, low dissociation constant --> effective for several days
5) UA, during PCI to prevent reoclusion, during primary rescue angioplasty in MI patients after thrombolytic txt failed
6) bleeding, reversed with platelet infusion

Front 26

Tirofiban
1) Drug class
2) Mechanism of action
3) Uses
4) Administration
5) Half life

Back 26

1) Antiplatelet
2) Binds GPII/IIIa platelet receptors, nonpeptide
3) Same indications as abcimixab: UA, PCI, primary angioplasty after failed thrombolytic therapy post MI.
4) IV only
5) High dissociation constant --> only active short period

Front 27

Eptifibatide
1) Drug class
2) Mechanism of action
3) Uses
4) Administration
5) Half life

Back 27

1) Antiplatelet
2) Binds GPII/IIIa platelet receptors, nonpeptide
3) Same indications as abcimixab: UA, PCI, primary angioplasty after
4) IV only
5) High dissociation constant --> only active short period

Front 28

Clopidogrel
1) Drug class
2) Mechanism of action
3) Benefits over predecessor
4) Metabolism
5) Administration
6) Adverse effects
7) Uses

Back 28

1) Antiplatelet
2) Irreversible inhibition of platelet ADP receptor --> inhibition of GP IIb/IIIa R --> no platelet aggregation
3) Less agranulocytoposis/neutropenia
4) Via liver to active metabolite, availability varies with patient
5) orally, active in 2 hrs, steady state 3-7 days
6) As above plus GI and intracranial hemmorhage
7) ACS, Acute MI, TIA, Stable Angina, Peripheral arterial disease

Front 29

Thrombolytic therapy:
1) Natural thrombolysis players?
2) Uses of thrombolytic therapy

Back 29

1) tPA released from endothelium activates plasminogen bound to fibrin clot to plasmin which cleaves fibrin to fibrin degradation products.
2) DVT, Pulmonary embolism, peripheral arterial occlusion, acute MI, Acute Stroke (admin within 3 hrs of stroke decreases mortality and improves function)

Front 30

Streptokinase
1) Drug class
2) Mechanism of action
3) Admin/half life

Back 30

1) Thrombolytic agent
2) Binds to fibrin bound and plasma plasminogen and converts it to plasma. Fibrin bound plasma breaks up clot. Plasma plasmin also helps lyse clot and also breaks up other plasma proteins like fibrinogen --> prolytic state that can lead to bleeding.
3) Short half life --> must be infused for long periods of time from 1 hr to 24 hr.

Front 31

Streptokinase
4) Determinants of success of streptokinase thrombolysis

Back 31

4)
a) Time: the earlier the better b/c early fibrin deposits can be broken down more easily than old cross linked fibrin.
b) Characteristic of thrombus: Easier in a thrombus that does not completely occlude the lumen.
c) Reocclusion after reperfusion. Can be prevented by:
-prolonged infusion periods
-anticoagulation with heparin
-antiplatelet with aspirin
-angioplasty to remove stenosis after thrombolysis

Front 32

Streptokinase
5) Adverse effects

Back 32

5) -Bleeding due to coagulation impairment
-Antigenicity due to foreign bacteria (product of strep)
-allergic rx

Front 33

APSAC
1) Drug class
2) Mechanism of action
3) Benefits over streptokinase?

Back 33

Anisolated streptokinase, anistreplase
1) Thrombolytic
2) Activated plasminogen
3) anisoyl group forms temporary protection of catalytic center of enzyme complex --> slows down the activity of the complex. Half life is longer, 90 min than streptokinase and can be administered for only 2-5 min. Also allows complex to localize to clot more. but still have lytic state

Front 34

Urokinase
1) Drug class
2) Mechanism of action
3) Administration/half life
4) Adverse effects
5) Benefit over streptokinase?

Back 34

1) Thrombolyic
2) trypsin like protease naturally made in kidney activates plasminogen. More fibrin specific than streptokinase
3) Short half life --> infused
4) General lytic state --> bleeding
5) Non antigenic

Front 35

rtpa
1) Drug class
2) Mechanism of action
3) Administration/half life
4) Adverse effects
5) Advantages over streptokinase

Back 35

1) Thrombolytic
2) acts like tissue tpa to activated plasminogen and is relatively fibrin specific
3) Short half life --> infusion necessary over long periods of time at high concentrations which can decrease fibrin specificity --> fibrinogen breakdown and lytic state
4) Bleeding, reoclusion post infusion (can be helped by coumadin, aspirin)
5) More fibrin specifc

Front 36

Time course for thrombolytic therapy in MI:
1) Time course for best functional results?
2) Time course for best mortality results?

Back 36

1) W/in 2 hrs of MI
2) W/in 3 hrs of MI