L20- Drugs Used in Disorders of Coagulation

Question 1

list the 3 steps hemostasis

Answer 1

1) primary hemostasis- platelet aggregation
2) secondary hemostasis- coagulation
3) fibrinolysis: via plasmin

Question 2

plasmin breaks down….

Answer 2

• fibrinogen
• fibrin

=> degradation products

Question 3

what are the types / functions of drugs used in disorders of coagulation

Answer 3

1) drugs used to reduce clotting

2) drugs used to reduce bleeding

Question 4

what are the types of drugs used to reduce clotting

Answer 4

• platelet aggregation inhibitors
• anticoagulants
• thrombolytics

Question 5

platelet aggregation inhibitors act on…..

Answer 5

• dec platelet synthesis

- inhibit actions of chemical signals

Question 6

what are the 4 platelet aggregation inhibitors

Answer 6

• cyclooxygenase inhibitors
• ADP receptor blockers
• phosphodiesterase inhibitors
• blocker of platelet GP IIb/IIIa receptors

Question 7

ASA functions as a (1) inhibitor via (2) interaction. The end goal and result is to decrease (3) levels which are responsible for (4).

Answer 7

1- COX (1 and 2)
2- irreversible acetylation
3- TX-A2
4- platelet degranulation and aggregation // vasoconstriction

Question 8

describe the platelet aggregation interaction

Answer 8

1 fibrinogen binding to 2 GP IIb/IIIa on 2 different platelets

note- this reaction / interaction occurs as a result of Ca influx

Question 9

ASA is used for…..

Answer 9

• prophylactic Tx of TIA/CVA (transient cerebral ischemia)

- reduce incidence of recurrent MI / dec mortality in post-MI patients

Question 10

(1) and (2) are the ADP receptor blockers that work via a (3) interaction with (4).
- indicate whether (1)/(2) is preferred and why

Answer 10

1- clopidogrel (preferred b/c fewer adverse effects)
2- ticlopidine
3- irreversible
4- P2Y12 (one of two ADP receptors)

Question 11

Clopidogrel is a prodrug that is converted to active metabolite via (1). List the contraindications for using clopidogrel, (2).

Answer 11

1- CYP2C19

2: (do not use….)
- in poor CYP2C19 metabolizers
- with Omeprazole, a CYP2C19 inhibitor

Question 12

clopidogrel is used for….

Answer 12

reduce rate of stroke, MI, death in patients with recent MI, stroke OR with acute coronary syndrome

Question 13

list the 2 phosphodiesterase inhibitors and their associated uses

Answer 13

• Dipyridamole: stroke prevention

- Cilostazol: intermittent claudication

Question 14

list the blockers of platelet GP IIb/IIIa receptors (indicate preferred drug) and what they treat

Answer 14

Abciximab, Eptifibatide, Tirofiban** (preferred)

-adjuncts in PCI (stent/angioplasty) for prevention of cardiac ischemic complications

Question 15

list anticoagulants

Answer 15

• indirect thrombin (IIa) and factor Xa inhibitors
• vitamin K antagonist
• direct thrombin (IIa) inhibitors
• direct factor Xa inhibitors

Question 16

list the indirect thrombin (IIa) and factor Xa inhibitors

Answer 16

• unfractionated heparin (UFH)
• low molecular weight heparins (LMWH)
• fondaparinux

Question 17

UFH and LMWH are administered via (1), it has a (fast/slow) action and used for (3)

Answer 17

1- injectable
2- rapid
3- interfere with formation of thrombi

Question 18

UFH and LMWH:

1) describe structure (+ weight
(2) explain source

Answer 18

1- mixture of straight-chain sulfated mucopolysaccharides (highly sulfonated => very negative)
-UFH: 5000-30000 MW
-LMWH (enoxaparin): 1000-5000 MW
2- isolated from bovine lung or porcine intestinal mucosa

Question 19

compare pharmacokinetic factors of UFH and LMWH

Answer 19

-equal efficacy

LMWH: higher bioavailability, longer half-life, requires less frequent dosing requirements

LMWH are becoming more preferred

Question 20

heparin binds and accelerates the action of (1) which will inhibit (2)

Answer 20

1- antithrombin III

2- thrombin (IIa), IXa, Xa

Question 21

(T/F) UFH and LMWH inactivate factor IIa and Xa equally

Answer 21

F:

• UFA inhibits both IIa, Xa (due to ternary complex formation with antithrombin III)
• LMWF inhibits Xa&raquo_space;> IIa (does not form ternary complex with antithrombin III)

Question 22

_____ is used to monitor the performance of Heparin

Answer 22

aPTT: activated partial thromboplastin time (integrity of the intrinsic / common pathways)

-LMWH usually doesn’t need monitoring, assessed with anti-factor Xa assays

Question 23

list the uses of heparin

Answer 23

-DVT
-pulmonary embolism
-MI
(drug of choice during pregnancy)

Question 24

list the adverse effects of heparin

Answer 24

• bleeding
• hypersensitivity reactions
• HIT (heparin induced thrombocytopenia: type II worse than benign type I)

Question 25

how does heparin cause type II HIT

Answer 25

(heparin induced thrombocytopenia) - antibodies recognize heparin and platelet protein (Platelet Factor 4) complex - Ig binds complex and activates Fc receptor on platelet => platelet aggregation and release of platelet contents (positive feedback) -thrombocytopenia and thrombosis

Question 26

heparin overdose or bleeding is treated with.....

Answer 26

protamine sulfate (positively charged, mops up heparin)

Question 27

Fondaparinux: (1) structure (2) binds to??? (3) inhibitor of???

Answer 27

1- synthetic pentasaccharide (sequence 5 carbohydrates) 2- antithrombin III 3- factor Xa specifically

Question 28

(1) is the vitamin K antagonist by inhibiting (2) so that factors (3) will not have (4)

Answer 28

1- warfarin 2- vitamin K epoxide reductase 3- II, VII, IX, X 4- γ-carboxyglutamyl side chains

Question 29

warfarin effects factor _____ the most

Answer 29

factor VII, extrinsic pathway (+ protein C, intrinsic pathway)

Question 30

warfarin is used to treat and prevent (1) and (2) following (3) or used to treat (4) used alone

Answer 30

1- DVT 2- pulmonary embolism 3- heparin 4- thromboembolic AFib

Question 31

list the adverse effects of warfarin

Answer 31

- hemorrhage - cutaneous necrosis (due to reduced protein C activity) - category X in pregnancy (hemorrhagic disorder in fetus, and serious birth defects)

Question 32

list the parenteral DTIs, include how it is monitored and what it is used for

Answer 32

(direct thrombin inhibitors) - desirudin - bivalirudin - argatroban - monitor via aPTT - used in patients undergoing PCI

Question 33

list the oral DTIs, include how it is monitored and what it is used for

Answer 33

(direct thrombin inhibitors) -dabigatran etexilate (prodrug converted to dabigatran) - no monitoring necessary - prevents and treats DVT, pulmonary embolism

Question 34

list the direct factor Xa inhibitors, include route of administration, how it is monitored, and what it is used for

Answer 34

-apixaban, rivaroxaban - oral - no monitoring necessary - prevents and treats DVT, pulmonary embolism

Question 35

why are direct thrombin and factor Xa inhibitors better than Warfarin

Answer 35

(dabigatran, apixaban, rivaroxaban) - equivalent antithrombotic efficacy - lower bleeding rate - quicker onset of action - predictable pharmacokinetics - wider therapeutic window - no monitoring required - fewer drug interactions

Question 36

why are thrombolytics (fibrinolytics) useful in comparison to anticoagulants

Answer 36

- lyses existing blood clots --> restores vessel patency before distal tissue necrosis - anticoagulants only prevent thrombi formation (acts by converting plasminogen to plasmin)

Question 37

list all the thrombolytics (how do they act)

Answer 37

- streptokinase, urokinase (non-fibrin selective) - alteplase, reteplase, tenecteplase (fibrin selective) - *they convert plasminogen to plasmin

Question 38

streptokinase is a (1) type drug found in (2) and is used for (3)

Answer 38

1- thrombolytic 2- β-hemolytic streptococci 3- rarely used

Question 39

urokinase is a (1) type drug found in (2) and is used for (3)

Answer 39

1- thrombolytic 2- human kidney (+ urine) 3- lysis of pulmonary emboli

Question 40

describe the MOA of alteplase, reteplase, tenecteplase

Answer 40

- t-Pa: tissue plasminogen activator, serine protease produced by human endothelial - t-Pa activates plasminogen bound to fibrin - t-Pa is 'fibrin selective'

Question 41

list the uses for alteplase, reteplase, tenecteplase

Answer 41

Alteplase: recombinant t-Pa, used for acute MI, acute ischemic stroke -Reteplase, Tenecteplase: recombinant variants of t-Pa, longer half-lives

Question 42

list the drugs used to treat bleeding

Answer 42

- plasminogen activator inhibitors - protamine sulfate - vitamin K - plasma fractions

Question 43

The main plasminogen activation inhibitors are (1) and (2). They are used in (3) and (4).

Answer 43

1- aminocaproic acid 2- tranexamic acid 3- adjunct hemophilia therapy 4- therapy to counter bleeding via fibrinolytic therapy

Question 44

(1) is a chemical antagonist of heparin because its structure is highly composed of (2)

Answer 44

1- protamine sulfate | 2- arginine, high positive charge

Question 45

vitamin K__ is administered in ______ fashion at birth

Answer 45

vitamin K1, injected IM at birth

Question 46

Vitamin K is used to treat (1) via (2) administration. It takes (3) for the onset of effect which lasts (4). If immediate hemostasis is required then (5) can be used.

Answer 46

``` 1- drug induced hypoprothrombinemia 2- oral, parenteral 3- 6 hrs 4- 24 hrs 5- fresh frozen plasma can be infused ```

Question 47

plasma fractions are used to (1), most commonly (2) and (3)

Answer 47

1- replace deficient coagulation factors 2- factor VIII 3- factor IX (2/3- mostly inherited conditions)