Antiplatelet & Anticoagulant Drugs

Front 1

What is the MOA of Aspirin?

Back 1

Aspirin (in portal circulation) irreversibly inhibits COX-1 of platelets via acetylating the active site; this prevents the formation of TXA2

Salicylate (product of Aspirin's 1st pass metabolism) reversibly inhibits COX-1 & COX-2 in the body; t1/2 is only 2-3 hours so platelet aggregation is only impaired for 8-12 hours

Front 2

What is the effect of Aspirin on the bleeding time, aPTT, PT?

Back 2

Bleeding time: increased
aPTT: no change
PT: no change

Front 3

A single dose of Aspirin must be taken _________ in order to exert an antithrombotic effect.

Back 3

Daily

Front 4

______ /day completely inhibits all platelet TXA2 synthesis in most patients

Back 4

160 mg

Front 5

If Aspirin escapes first pass metabolism and enters the circulation as acetylsalicylic acid, it could irreversibly inhibit the COX-1 in vascular endothelial cells that normally synthesize ________.

Back 5

PGI-2

Front 6

A small daily dose of Aspirin (______ mg) produces a persistent antithrombotic effect b/c it ?

Back 6

Irreversibly inhibits the production of TXA2 by platelets w/o affecting the synthesis of PGI2 by the VECs

*This is the answer for any exam*

Front 7

Very large doses of Aspirin (6+ g/day) can increase the aPTT by inhibiting?

Back 7

Hepatic synthesis of clotting factors

Front 8

What drugs are antagonists of the IIb/IIIa receptor?

Back 8

Abciximab
Tirofiban
Eptifibatide

Front 9

What is the MOA of the glycoprotein IIb/IIIa receptor antagonists?

Back 9

Blocks the IIb/IIIa receptors by which fibrinogen binds platelets together--platelet aggregation is blocked

Block platelet aggregation caused by any factor--collagen, TXA2, Thrombin

Front 10

What are the medical uses of the IIb/IIIa antagonists?

Back 10

1. Prophylacticly for PCI
2. Acute coronary syndrome--acute MI, unstable angina
-chest pain
-abnormal ECG (ST depression)
-elevated cardiac enzymes

Front 11

What are the adverse effects of IIb/IIIa receptor antagonists?

Back 11

Bleeding

Front 12

What drugs are purinergic (ADP) receptor antagonists?

Back 12

1. Ticlopidine
2. Clopidogrel

Front 13

What is the MOA of Ticlopidine/Clopidogrel?

Back 13

Both drugs block the P2Y(12) purinergic receptor of platelets and this block platelet aggregation

Front 14

ADP stimulation of the PY2(1) receptor of platelets results in what?

Back 14

Activation of Phospholipase C

Leads to the synthesis of IP3

Calcium is released from the sarcoplasmic reticulum and a change in the shape of platelets occurs

Platelets aggregate

Front 15

ADP stimulation of the PY2(12) receptor results in what?

Back 15

Inhibition of adenyl cyclase leading to decreases cAMP

*cAMP inhibits platelet aggregation by lowering the free intracellular concentration of calcium

Front 16

What drug is an irreversible PY2(12) receptor inhibitor that permanently inactivates the receptor?

Back 16

Clopidogrel

Front 17

Ticlopidine/Clopidogrel are used with _________ during PCI.

Back 17

Aspirin

Front 18

What drug is used to treat patients who cannot take Aspirin b/c of Aspirin hypersensitivity or who have failed therapy on Aspirin?

Back 18

Ticlopidine/Clopidogrel

Front 19

Ticlopidine must be give for _____ days to achieve its full antiplatelet effect.

Back 19

10

Front 20

What are other medical uses of the ADP receptor antagonists?

Back 20

1. decrease incidence of MI and stroke in patients with atherosclerotic vascular disease

2. used to prevent thrombosis in patients with a previous ischemic stroke

3. used to prevent MI in patients with unstable angina

4. given w/ Aspirin to reduce secondary MI by an additional 9%

Front 21

What are the adverse effects of Ticlopidine & Clopidogrel?

Back 21

Ticlopidine: neutropenia (1%), thrombocytopenia, agranulocytosis

Clopidogrel: much lower incidence of neutropenia and agranulocytosis

Front 22

What is the MOA of Heparin with regards to Platelet function?

Back 22

Blocks adhesion of platelets by maintaining the electronegativity of the damaged vascular wall

Prevents platelet adhesion, aggregation and the "release" reaction

Front 23

What is the main goal of anticoagulant therapy?

Back 23

Prevent the activation of Prothrombin (II) to Thrombin (IIa)

Front 24

What is the composition of unfractionated Heparin?

Back 24

Mixture of HMG glycosaminoglycans

Front 25

The circulating protein __________ is a weak inhibitor of activated clotting factors in the absence of heparin.

Back 25

AT III

Front 26

AT III is a _____________ of the activated clotting factors

Back 26

Suicide inhibitor

Front 27

What is the MOA of Heparin?

Back 27

Binding of Heparin to AT III induces a conformational change in AT III which makes this critical peptide bond of AT III more accessible to the protease site of the activated clotting factor

Front 28

The presence of heparin causes a ________ X increase in the rate of interaction between AT III and the activated clotting factors

Back 28

1000

Front 29

What happens to heparin after the heparin-ATIII complex is attacked by a clotting factor?

Back 29

Heparin is released and is able to bind to another molecule of AT III

*heparin functions as a catalyst in the reaction

Front 30

Heparin inhibits the protease activity of clotting factors:

Back 30

2, 9, 10, 11, 12

Front 31

How do you access the pharmacodynamic effect of heparin?

Back 31

Measure the aPTT which measures the activity of the clotting factors that are intrinsic to plasma--primarily the activity of factor IIa (Thrombin)

Front 32

Why can the anticoagulant activity of Warfarin be quantified in the presence of Heparin?

Back 32

Heparin does not affect the value of the PT

Front 33

How long does it take for Heparin to exert an anticoagulant effect?

Back 33

Immediately

Front 34

What drug binds avidly to Heparin and prevents its interaction with AT III?

Back 34

Protamine Sulfate

Front 35

Why should no more than 50 mg of Protamine Sulfate be given?

Back 35

Protamine Sulfate itself possesses some anticoagulant activity

Front 36

How is Protamine Sulfate administered? When do the effects occur?

Back 36

1. i.v.
2. immediately

Front 37

What drugs are the LMW heparins?

Back 37

Ardeparin
Dalteparin
Enoxaparin

Front 38

What is the MOA of LMW Heparins?

Back 38

Bind to AT III and primarily inhibits activated factor 10 (Xa)

*exert no effect against IIa, so aPTT is NOT increased

Front 39

Normal heparin is of sufficient molecular size to bind both _______ & _______ simultaneously, but the LMW heparins are too small to do this.

Back 39

1. ATIII
2. IIa

Front 40

What is the effect of Protamine Sulfate on LMW heparins?

Back 40

Effects are only partially reversed

Front 41

What are the routes of administration of Heparin?

Back 41

i.v. bolus

constant i.v.

s.c. injection

Front 42

Heparin in plasma is cleared by the _____________ .

Back 42

Reticuloendothelial system

Front 43

The half-life of heparin (increases/decreases) as the dose is increased.

Back 43

Increases

Front 44

What is target aPTT for heparin therapy?

Back 44

1.5-2.5 the normal value

Front 45

How is the aPTT achieved in heparin therapy?

Back 45

i.v. loading dose followed by i.v. infusion of a maintenance dose

Front 46

How often should the aPTT be measured in a patient receiving heparin?

Back 46

Every 6 h

Front 47

During long term treatment, how often is Heparin given?

Back 47

every 8-12 h s.c.

Front 48

What are the causes of Heparin resistance?

*Important for exam*

Back 48

Increased clearance--occurs in pulmonary embolism

Genetic ATIII deficiency

Acquired ATIII deficiency--neprhotic syndrome, hepatic cirrhosis, DIC

Acute phase proteins released in response to inflammation can bind to heparin and render it inactive

Front 49

What is the antiplatelet affect of Heparin?

Back 49

Blocks platelet adhesion by maintaining the electronegativity of the damaged vascular wall

Front 50

What may Heparin do the the Bleeding Time?

Back 50

Increase

*effect is additive with that of Aspirin

Front 51

What are the therapeutic uses of unfractionated heparin?

Back 51

Prophylaxis of post-operative DVT

Treatment of DVT and PE

Prophylaxis during PCI

Relief from chest pain in pts. w/ unstable angina

Anticoagulant for i.v. catheters, hemodialysis, and cardiopulmonary bypass

Front 52

What is the anticoagulant drug of choice during pregnancy?

Back 52

Heparin--does not cross placental barrier, have teratogenic effects, or cause premature labor or fetal death

Front 53

Heparin should be discontinued _____ h before delivery.

Back 53

24

Front 54

What are the therapeutic uses of LMW heparins?

Back 54

Prophylaxis for post-operative DVT
Treatment of ischemic stroke
Acute coronary syndrome
Anicoagulant during hemodialysis

Front 55

What are the contraindications for Heparin & LMW heparins?

Back 55

Spinal anesthesia of lumbar puncture
Bleeding

Front 56

What are the adverse effects associated with heparin therapy?

Back 56

1. Bleeding; incidence is less w/ LMW heparins

2. Reversible heparin-induced thrombocytopenia

3. Osteoporosis w/ fractures after continuous treatment for 3+ months

4. Slight elevation of plasma K+ from inhibition of Aldosterone synthesis (may be a problem if patient is taking an ACE inhibitor)

Front 57

What is the mechanism of Heparin-induced thrombocytopenia?

Back 57

HIT is caused by the binding of IgG Ab to the platelet factor 4-heparin complex on the surface of platelets

IgG binding elicits platelet activation, aggregation, & the formation of platelet clots

The IgG in these platelet clots causes the clots to be cleared by the RES; this results in thrombocytopenia

Front 58

How is HIT diagnosed ?

Back 58

Platelet count falls to < 50% of the baseline value, or falls below 150k during heparin therapy

Front 59

Is HIT associated with thrombosis or bleeding?

Back 59

Thrombosis--20% of patients lose a limb, 30% die

Front 60

Patients with HIT need therapy with a non-heparin anticoagulant such as?

Back 60

Fondaparinux

Lepirudin

Argatroban

Front 61

What are the advantages of LMW heparins over unfractionated heparins?

Back 61

1. Kinetics not altered by binding to plasma proteins, acute phase proteins, endothelial cells or macrophages

2. Increased s.c. bioavailability and a longer half-life

3. Cleared by the Kidney, not the RE system

4. Cause less thrombocytopenia b/c fewer antiheparin Abs are formed

5. Patient can self-administer these drugs s.c. at home

6. When given s.c. q12h or qd, they produce a predictable & reproducible anticoagulant effect w/o the need for lab monitoring of hemostasis

Front 62

What is a drawback of LMW heparins compared to unfractionated heparin?

Back 62

Expensive & not yet covered by Medicare

Front 63

What is the MOA of Fondaparinux?

Back 63

Synthetic pentasaccharide which mimics the site on heparin which binds ATIII

Indirect factor Xa inhibitor--req. presence of ATIII

Produces a predictable, stable antithrombotic effect

Front 64

What is the route of administration of Fondaparinux? What is the F?

Back 64

s.c

F = 100%

Front 65

What is the half-life of Fondaparinux?

Back 65

17-21

Front 66

What is the effect of Fondaparinux on the bleeding time, aPTT, and the PT

Back 66

No effect

Front 67

Why is Fondaparinux superior to LMW heparin in the treatment of ACS?

Back 67

1. Less bleeding
2. Less re-infarction
3. Less morbidity/mortality

Front 68

What is the MOA of Lepirudin?

Back 68

DIRECT inhibitor of both free & clot-bound Thrombin

Binding to Thrombin is very tight and essentially irreversible

ATIII is not required for Lepirudin to inhibit Thrombin

Front 69

Lepirudin is administered i.v. at a dose which increases the aPTT to _________the normal value

Back 69

1.5 to 2.5 times

No effect on PT*

Front 70

What is the half-life of Lepirudin?

Back 70

1.3 h

*increased in pts. w/ renal failure

Front 71

What is the MOA of Argatroban?

Back 71

Small synthetic molecule which is a direct, competitive, REVERSIBLE inhibitor of thrombin (factor IIa)

Inhibits soluble, fibrin-bound, and clot-bound thrombin

Inhibits platelet aggregation & TXA2 release in the presence of both free & clot-bound thrombin

Front 72

What is the route of administration of Argatroban? Half-life?

Back 72

i.v. loading dose followed by constant i.v. infusion

40-50 minutes

Front 73

What is the affect of Argatroban on the aPTT?

Back 73

Increases to 1.5-3.0 X normal

aPTT returns to normal w/ in 1-2 h after discontinuation of drug

Front 74

What does Argatroban do to the PT when given alone? when given with Warfarin?

Back 74

alone: slightly increases the PT
w/ warfarin: greater increase; INR = 4

*no effect on bleeding time, but it does inhibit thrombin-induced platelet activation

Front 75

Clotting factors __________ require a post-translational gamma-carboxylation of 9 to 12 glutamate residues.

Back 75

2, 7, 9, 10

Front 76

The gamma carboxylation of factor 2,7,9, 10 is coupled to the oxidative metabolism of?

Back 76

Reduced Vitamin K --> Vit. K epoxide

Front 77

Why is the gamma carboxylation of factors 2,7,9,10 necessary?

Back 77

Extra carboxyl groups are needed to bind Ca2+ for activation

Front 78

How is reduced vitamin K regenerated from Vitamin K epoxide?

Back 78

Vitamin K Epoxide Reductase

Front 79

The enzyme vitamin K epoxide reductase is inhibited by ?

Back 79

Warfarin

Front 80

What is the result of Warfarin inhibiting vitamin K epoxide reductase?

Back 80

Depletion of reduced vitamin K eventually stops the post-translational modification of clotting factors 2,7,9,10

Front 81

How is the anticoagulant action of Warfarin gauged?

Back 81

Measuring the prothrombin time

(b/c the half-life of factor 7 is the shortest)

Front 82

How long does it take for the full anticoagulant effect of warfarin to take place?

Back 82

5 days

Front 83

Does Warfarin work in vitro?

Back 83

NO

Front 84

What does a therapeutic dose of Warfarin do to the aPTT?

Back 84

Does NOT prolong the aPTT

*overdose increases aPTT and INR

Front 85

What is the target INR of Warfarin therapy?

Back 85

2-3

Front 86

An INR > ______ may be required in patients with prosthetic heart valves receiving Warfarin therapy.

Back 86

3

Front 87

What happens at an INR > 4?

Back 87

BLEEDING

Front 88

The anticoagulant action of Warfarin can be reversed by:

Back 88

1. Phytonadione (reduced vitamin K)
2. Fresh frozen plasma (provides functional clotting factors)
3. Factor 9 concentrate (large amts of 2, 7, 9, 10)

Front 89

What is the route of administration of Phytonadione?

Back 89

i.v., s.c., or p.o.

Front 90

How long before a patient will see the effect of Phytonadione (reversal of anticoag. effect of Warfarin)?

Back 90

Several hours; may take 24 h for full reversal of the anticoagulant effect

*repeated doss of vitamin K are required to produce normal hemostasis after overdose with Warfarin

Front 91

Warfarin is _____% bound to plasma proteins, and numerous drug-drug interactions with Warfarin involve its displacement from plasma proteins.

Back 91

99

Front 92

Warfarin is biotransformed by?

Back 92

CYP2C9

Front 93

Is Warfarin teratogenic?

Back 93

Yes, category X, crosses the placental barrier

Front 94

The onset of action of Warfarin is _____ days, and the maximal effect is acheived at ______ days.

Back 94

2-3

5

Front 95

The goal of Warfarin therapy is to increase the INR to ______, and the INR should be measured __________ after patients are titrated to the desired value of the INR.

Back 95

Monthly

Front 96

What are the therapeutic uses of Warfarin?

Back 96

Prophylaxis of DVT after orthopedic surgery

Prophylaxis of thromboembolism in patients with
-atrial fibrillation
-prosthetic cardiac valves
-rheumatic mitral valve disease
-unstable angina

Front 97

How is the transition made from "in house" treatment with Heparin to outpatient treatment with Warfarin?

Back 97

A period of 4-5 days of overlapping therapy with heparin & warfarin is required before you can discharge the patient on p.o. therapy with Warfarin

Front 98

A patient could STILL be at risk for ________________ if heparin was discontinued only two days after therapy w/ Warfarin.

Back 98

Thromboembolism

Front 99

How can you eliminate the problem of prolonging hospitalization when converting from parenteral heparin to p.o. Warfarin?

Back 99

Self-administration of a LMW heparin

Front 100

What are the adverse effects of Warfarin?

Back 100

Bleeding

Teratogenesis and fetal death:
1. Ingestion during 1st tri. causes abnormal bone growth with nasal hypoplasia & stippled epiphyseal calcifications
2. Adversely effects the vitamin K-dependent synthesis of the protein Osteocalcin which is important for the mineralization of bone
3. Abnormalities of the CNS
4. Intrauterine or neonatal death b/c of hemmhorage

Cutaneous necrosis

Front 101

The fibrin net that hold a thrombus together is dissolved by the proteolytic enzyme ________ when vascular repair is complete.

Back 101

Plasmin

Front 102

Both t-PA released from vascular endothelial cells and the plasma protein plasminogen bind to ______ in fibrin.

Back 102

Lysine

Front 103

When bound to fibrin in close proximity, tPA activates ____________ to ____________

Back 103

Plasminogen to Plasmin

Front 104

The protease activity of Plasmin will also degrade (in addition to Fibrin)?

Back 104

Factors 5 & 8

Fibrinogen

Front 105

tPA in the plasma normally does not activate circulating plasminogen to plasmin bc the plasma proteins _______________ inhibit tPA

Back 105

Plasminogen activator inhibitors 1 & 2

Front 106

Any Plasmin that may be produced by an action of tPA in plasma is inhibited by the circulating protein:

Back 106

alpha-2-antiplasmin

*binds to lysine in fibrin and blocks the binding of plasminogen or plasmin
*protects the thrombus from degradation before vascular repair can be completed

Front 107

What is the MOA of t-PA?

Back 107

A serine protease that cleaves a single peptide bond of plasminogen to form plasmin

Front 108

Plasminogen and tPA possess ______________ for lysine residues that are exposed on Fibrin.

Back 108

Amino terminal binding sites

Front 109

What is drug is unmodified human t-PA produced by recombinant technology?

Back 109

Alteplase

Front 110

How does the i.v. injection of Alteplase produce a systemic fibrinolytic state?

Back 110

The enzymatic activation of plasminogen to plasmin is so great that the endogenous inhibitors of tPA and plasmin are overwhelmed and the specificty of plasmin for the fibrin in thrombi is lost.

A systemic fibrinolytic state ensures due to the degradation of clotting factors 5, 8, and fibrinogen

Front 111

What is the MOA of Streptokinase?

Back 111

The binding of streptokinase near the carboxy terminus of plasminogen induces a conformational change that exposes protease activity of plasminogen located near the amino terminus

Protease activity cleaves Plasmin from another plasminogen molecule

Plasmin can attack the fibrin in thrombi of circulating clotting factors 5 and 8 and fibrinogen

Front 112

Streptokinase and t-PA induced reperfusion decreases mortality by 30% after MI, but immediate _______, with or without intra-arterial stents, is superior to thrombolytic therapy.

Back 112

PCI

Front 113

The increased rate of survival from MI after treatment with a thrombolytic drug is enhanced by cotreatment with:

Back 113

UFH or LMWH

Aspirin and Clopidogrel

Beta-blocker: reduces infarct size and myocadial ischemia, prevents reinfarction and fatal ventricular dysrhythmias

ACE inhibitor: reduces preload & afterload to improve CO, reduces infarct size, prevents dysrhythmias

Nitrate--reduces preload and infarct size

Front 114

What are the therapeutic uses of fibrinolytic drugs?

Back 114

Establish reperfusion of coronary vessels after MI

Pulmonary embolism

DVTs

Ischemic stroke

Front 115

What toxicity is associated with fibrinolytic drugs?

Back 115

Bleeding due to the non-selective lysis of thrombi involved in normal vascular repair and the wide-spread degradation of clotting factors 5 & 8 and fibrinogen

Front 116

What is the MOA of Aminocaproic acid?

Back 116

Lysine analog that occupies the lysine-binding sites of plasmin, plasminogen, t-PA, alteplase and prevents them from binding to Fibrin in thrombi.

Front 117

What is the therapeutic use of Aminocaproic acid?

Back 117

Used to prevent bleeding caused by fibrinolytic therapy & the extracorporeal circulation of blood