Pharmacology - Coagulation

Front 1

Define Hemostasis

Back 1

- Hemostasis = cessation of blood loss from a damaged vessel
- Primary Hemostasis = platelet aggregation
- Secondary Hemostasis = coagulation

Front 2

Regulation of Hemostasis

Back 2

- 2 systems regulate blood coag and thrombus formation:
(i) Fibrin Inhibition - plasma contains protease inhibitors that inactivate the coagulation proteins
(ii) Fibrinolysis - inactive plasminogen is converted to proteolytic enzyme plasmin --> digests fibrin

Front 3

Drugs used to reduce clotting: Platelet aggregation inhibitors

Back 3

- decrease synthesis or action of chemical signals that promote platelet aggregation
- include:
Cyclooxygenase inhibitors
ADP Receptor blockers
Phosphodiesterase inhibitors
Blockers of platelet GP IIb/IIIA receptors

Front 4

Cyclooxygenase inhibitors

Back 4

ASPIRIN
- inhibits thromboxane A2 synthesis by irreversible acetylation of enzyme COX
- thromboxane A2 causes platelets to degranulate and to aggregate
- b/c platelets dont have a nucleus, they cant synthesize any new proteins during its 10-day lifetime

Front 5

Cyclooxygenase inhibitors - Aspirin - Uses

Back 5

- prophylactic tx of transient cerebral ischemia
- reduce incidence of recurrent MI
- decrease mortality in post MI pts

Front 6

ADP Receptor blockers

Back 6

CLOPIDOGREL & TICLOPIDINE
- irreversible inhibitors of P2Y12 (subtype of ADP receptor on platelet surface)
- clopidogrel has less AE and is preferred over ticlopidine

Front 7

Phosphodiesterase inhibitors

Back 7

DIPYRIDAMOLE
- coronary vasodilator
- prophylactically treat angina pectoris
- inc cAMP by inhibiting phosphodiesterase and/or by blocking uptake of adenosine, which acts at A2 receptors to activate adenylyl cyclase

Front 8

Phosphodiesterase inhibitors - Dipyridamole - Uses

Back 8

- by itself has little use
- used in comb w/ warfarin for thromboemboli in pts w/ prosthetic heart valves
- used in comb w/ aspirin for secondary prophylaxis of cerebrovascular disease

Front 9

Blockers of Platelet GP IIb/IIIA Receptors

Back 9

- used in pts w/ acute coronary syndromes
- IIb/IIIa complex = receptor for fibrinogen, vitronectin, fibronectin, and vWF
- activation of this receptor = final common pathway for platelet aggregation

Front 10

Blockers of Platelet GP IIb/IIIA Receptors - Drugs

Back 10

ABCIXIMAB
- Monoclonal Ab directed against human GP IIb/IIIa receptor
EPTIFIBATIDE
- cyclic peptide reversible antagonist of the GP IIb/IIIa receptor
TIROFIBAN
- nonpeptide reversible antagonist of the GP IIb/IIIa receptor

Front 11

Drugs used to reduce clotting: Anticoagulants

Back 11

- Unfractionated Heparin and low-molecular wt Heparins
- Selective Factor Xa Inhibitors
- Direct Thrombin Inhibitors (DTIs)
- Coumarin anticoagulants

Front 12

Heparin - General info

Back 12

- Injectable, rapidly acting anticoag. often used acutely to interfere w/ formation of thrombi
- mix of straight-chain anionic glycosaminoglycans

Front 13

Heparin - MOA

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- Usually, antithrombin III (an alpha-globulin) inhibits serine proteases, including several clotting factors like thrombin
- In absence of heparin, antithrombin III interacts w/ thrombin very slowly
- binding of heparin to antithrombin III allows antithrombin to rapidly inhibit thrombin EXCEPT that already bound to fibrin

Front 14

Low-molecular-weight Heparin (LMWH)

Back 14

- inhibits activated factor X
- less effect on thrombin than UFH

Front 15

Monitoring of Heparin

Back 15

- done by activated partial thromboplastin time (aPTT) assay
- aPTT = test of integrity of intrinsic and common pathways of coagulation
- LMWH has higher therapeutic index than unfractionated heparin especially when used for prophylaxis (not necessary to monitor LMWH levels)

Front 16

Heparin - AE

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- Bleeding
- Hypersensitivity rxns
- Thrombosis (b/c reduced antithrombin III activity)
- Heparin-induced Thrombocytopenia (HIT) Type II

Front 17

Heparin-induced Thrombocytopenia (HIT) Type II

Back 17

- Ab recognize complexes of heparin and a platelet factor 4 --> platelet aggreg and release of platelet contents
- can result in thrombocytopenia and thrombosis
- therapy = discontinue heparin and admin of a DTI or fondaparinux

Front 18

Reversal of Heparin Action

Back 18

- discontinuance
- if bleeding: protamine sulfate given

Front 19

Selective Factor Xa Inhibitors

Back 19

FONDAPARINUX
- pentasaccharidde
- sequence of 5 carbs necessary for binding to antithrombin III
- specific inhibitor of Xa
- negligible antithrombin activity
- tx of DVT

Front 20

Direct Thrombin Inhibitors (DTIs)

Back 20

- directly bind to active site of thrombin
- include:
LEPIRUDIN
BIVALIRUDIN
ARGATROBAN

Front 21

Lepirudin

Back 21

- hirudin = specific thrombin inhibitor from the leech!
- available in recomb form as lepirudin
- action independent from antithrombin III
- monitored by aPTT
- NO antidote exists

Front 22

Bivalirudin

Argatroban

Back 22

Bivalirudin = synthetic derivative of hirudin

Argatroban = small molecule thrombin inhibitor

Front 23

Coumarin anticoagulants

Back 23

WARFARIN and DICUMAROL
- called oral anticoags b/c unlike heparin they are given orally

Front 24

Warfarin and Dicumarol - MOA

Back 24

- inhibit vit K epoxide reductase --> prod of inactive clotting factors (lack gamma-carboxyglutamyl side chains)
- takes 8-12 hrs
- can be overcome with vit K (24 hrs)

Front 25

Monitoring Warfarin levels

Back 25

- narrow TI; many drug-drug interactions
- monitoring performed w/ the prothrombin time (PT)
- test of extrinsic and common pathways of coagulation
- warfarin prolongs PT (b/c it dec amt of functional factor VII)

Front 26

Warfarin and Dicumarol - AE

Back 26

- Hemorrhage
- Cutaneous necrosis w/ reduced activity of protein C
- Warfarin crosses the placenta
- Warfarin should NEVER be admin w/ pregnancy

Front 27

Drugs used to reduce clotting: Thrombolytics (fibrinolytics)

Back 27

- lyse thrombi by catalyzing conversion of plasminogen --> plasmin
- reduce mortality of acute MI
STREPTOKINASE
UROKINASE
ALTEPLASE, RETEPLASE, & TENECTEPLASE
ANISTREPLASE

Front 28

Drugs used to treat bleeding

Back 28

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

Front 29

Plasminogen activation inhibitors

Back 29

AMINOCAPROIC ACID
- inhibits plasminogen activation

Front 30

Protamine sulfate

Back 30

- antag of heparin
- high in arginine
- forms complex w/ heparin with no anticoagulant activity
- inactive against fondaparinux

Front 31

Vitamin K

Back 31

- can stop oral anticoags
- 24 hrs
- if immediate hemostasis needed, fresh-frozen plasma should be infused

Front 32

Plasma Fractions

Back 32

- Def in plasma coag factors can cause bleeding
- Factor VIII deficiency (classic hemophilia, or hemophilia A) and factor IX def (Christmas disease or hemophilia B) account for most of the heritable coagulation defects