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Flashcards in Anti-platelets & fibrinolytics Deck (64):
1

Platelet aggregation is physiologically facilitated by

- thromboxane (TXA2)
- ADP receptor stimulation
- GP IIb/IIIa receptor stimultation

2

platelet aggregation is pharmacologically inhibited by

- TXA2 synthesis inhibitor aspirin
- ADP receptor antagonists Ticlopidine and Clopidogrel
- dipyridamole
- GP IIb/IIIa receptor antagonists Abciximab

3

Use of aspirin & MOA

low dose aspirin (81-325)
Use: antiplatelet

MOA: irreversibly inhibit platelet COX enzyme by acetylating the enzyme and also inhibits thromboxane synthetase
- as platelets cannot synthesize new COX (no nucleus)
- no thromboxane TXA2 synthesis
- antithrombotic effect lasts for 3 days

High dose aspirin = COX 1 and 2

Use: low dose daily prevents ischemic attack and MI

>1000mg/day has NO anti platelet effect

- high dose is anti-inflammatory dose
- high dose inhibits prostacyclin (PGI) synthesis
- PGI normally prevents platelet aggregation
- therefore prophylactic benefit of aspirin as an anti platelet drug is always in low doses

MC use of aspirin = coronary artery disease

4

COX 1

COX1 = housekeeping; important with PG in mucous production

aspirin-induced ulcers result from inhibition of this --> not seen much with low-dose aspirin

Remember: aspirin acetylates serine residue on COX --> inhibits TXA2 synthetase

5

Ticlopidine: MOA, use, A/E

ADP receptor antagonist

MOA: blocks platelet ADP receptor and prevents platelet aggregation

Uses:
- for prevention of TIA, post MI, unstable angina and as an alternative to aspirin
- adjunct therapy with aspirin following coronary stent implantation to decrease incidence of stent thrombosis

A/E:
- severe neutropenia, thrombocytopenic purpura

6

GP IIb/IIIa receptor antagonists

- Abciximab
- Eptifibatide
- Tirofiban

7

Fibrinolytics / Thrombolytics

- streptokinase
- urokinase
- tissue plasminogen activator (tPA)

fibrinolytic therapy should be used ASAP to reestablish blood flow following AMI; >60% decrease in mortality post-MI if used within 3 hours!

8

Antifibrinolytics

aminocaproic acid
tranexamic acid

9

Clopidogrel: MOA, use, A/E

ADP receptor antagonist

MOA: blocks platelet ADP receptor and prevents platelet aggregation

Uses:
- for prevention of TIA, post MI, unstable angina and as an alternative to aspirin
- adjunct therapy with aspirin following coronary stent implantation to decrease incidence of stent thrombosis

A/E:
- less incidence of neutropenia or thrombocytopenia

10

Eptifibatide: MOA and use

GP IIb/IIIa receptor antagonist

MOA: Inhibit binding of fibrinogen to the GPIIb/IIIa receptor --> thereby inhibiting the final, common pathway of platelet aggregation

Use: given along with aspirin and heparin during coronary angioplasty (PTCA)
- markedly reduce the incidence of restenosis

11

Streptokinase

thrombolytic/fibrinolytic

- obtained from streptococci

MOA: binds to circulating plasminogen--> converts to plasmin

A/E: bleeding, allergic reactions, hypotension, fever

12

alteplase

tPA

MOA: binds to & activates fibrin bound plasminogen (more local action on the thrombus)

13

Dipyridamole MOA

Inhibits phosphodiesterase --> increased cAMP --> prevents aggregation

14

Abciximab:

GP IIb/IIIa receptor antagonist

MOA: monoclonal antibodies directed against GP IIb/IIIa receptor complex

Use: given along with aspirin and heparin during coronary angioplasty (PTCA)
- markedly reduce the incidence of restenosis

15

urokinase

fibrinolytic/thrombolytic
- derived from human tissue

16

reteplase

tPA

MOA: binds to & activates fibrin bound plasminogen (more local action on the thrombus)

17

aminocaproic acid: MOA, Uses

antifibrinolytic

MOA: Inhibits the plasminogen activation

Uses: to treat excessive bleeding due to overdose of fibrinolytic agents

18

Tissue plasminogen activator (tPA)

fibrinolytic/thrombolytic
- Alteplase, reteplase (recombinant DNA technology)

MOA: binds to & activates fibrin bound plasminogen (more local action on the thrombus)

used to help re-canalize bv after AMI

19

Tirofiban: MOA and use

GP IIb/IIIa receptor antagonist

MOA: monoclonal antibodies directed against GP IIb/IIIa receptor complex

Use: given along with aspirin and heparin during coronary angioplasty (PTCA)
- markedly reduce the incidence of restenosis

20

tranexamic acid: MOA, Uses

antifibrinolytic

MOA: Inhibits the plasminogen activation

Uses: to treat excessive bleeding due to overdose of fibrinolytic agents

21

Anticoagulants

- Heparin
- warfarin (Oral anticoagulant)
- dicumarol (Oral anticoagulant)
- hirudin (direct thrombin inhibitor)
- bivalirudin (direct thrombin inhibitor)

22

heparin: MOA, Pharmacokinetics,

Anticoagulant: indirect thrombin inhibitor
- unfractionated Heparin (UFH)
- low molecular weight heparins (LMWH)--longer DOA
- monitor via aPTT

MOA: activates ATIII --> inactivates clotting factors in intrinsic pathway
- thrombin IIa, IXa, Xa

Pharmacokinetics:
- hepatin is a strong acid and can be neutralized by basic compounds like protamine***
- highly ionized --> not absorbed orally
--> does not cross placenta; safe in pregnancy*
- given via IV/ S.C.

- dose monitored by aPTT (activated partial thromboplastin time) --> normally 25-39 sec

- with heparin: 45-75 sec; beyond this-->bleeding!

23

warfarin

Oral Anticoagulant

24

intrinsic coagulation system

Intrinsic pathway: factors XII, XI, IX, and VIII
- begins with activation of factor XII (Hageman factor)
- exposed sub-endothelial collagen and HMWK activate factor XII to form factor XIIa
- factor XIIa is also known as activated Hageman factor
- factor XIIa activates factor XI to form factor XIa
- factor XIIa activates 3 substances:
---> factor XI to form factor XIa
---> plasminogen to form plasmin
---> kininogen system to produce chalkier and bradykinin

- XIa activates factor IX to form IXa
- IXa complexes with factor VIII, CA2+, and PF3 to form a four component complex: factor IXa, factor VIII, PF3 and Ca2+
- in the final common pathway this complex activates factor X
_____________________________________________
XII --> XIIa
XI --> XIa
IX --> IXa
VIII + IXa + PF3 + Ca2+ --->common pathway

Common pathway:
X --> Xa
V + Xa + PF3 + Ca2+
prothrombin --> thrombin
fibrinogen --> fibrin monomer
fibrin monomer aggregate--> soluble fibrin --> cross-linked insoluble fibrin

25

extrinsic coagulation pathway

Extrinsic pathway: factor VII
- begins with activation of factor VII
- Tissue Thromboplastin released from injured tissue activates factor VII resulting in formation of factor VIIa
- in the final common pathway factor VIIa activates factor X
_______________________________________
VII --> VIIa
----> common pathway:
X --> Xa
V + Xa + PF3 + Ca2+
prothrombin --> thrombin
fibrinogen --> fibrin monomer
fibrin monomer aggregate--> soluble fibrin --> cross-linked insoluble fibrin

26

dicumarol

Oral anticoagulant

27

Common Pathway

Factors X, V, II (prothrombin) and I (fibrinogen)
- begins with activation of factor X by:
--> factor VIIa (extrinsic pathway)
--> four component complex [(factor IXa, factor VIII, PF3, Ca2+) intrinsic pathway]
-activated factor Xa complexes with factor V, PF3, and Ca2+ to form a complex = the Prothrombin complex
----> prothrombin complex cleaves prothrombin to the enzyme thrombin
_____________________________________
X --> Xa
V + Xa + PF3 + Ca2+
prothrombin --> thrombin
fibrinogen --> fibrin monomer
fibrin monomer aggregate--> soluble fibrin --> cross-linked insoluble fibrin

28

LMW heparins: names, MOA, Advantages, A/E

enozaparin
dalteparin
tinzaparin

- selectively inhibit Xa, less effect on thrombin
- given subcutaneously

advantages:
- less hemorrhagic complication, less thrombocytopenia
- equally efficacious
- increased bioavailability
- less frequent dosing, bc longer half life
- less effect on aPTT

A/E: BLEEDING!
- close monitoring of activated partial thromboplastin time (aPTT)
- PROTAMINE is used to stop bleeding due to heparin
- Moderate & transient thrombocytopenia --> immune mediated
- Osteoporosis on prolonged use

29

Hemopoietic agents used in treatment of anemias and hemopoietic growth factors

- iron
- vitamin B12
- folic acid
- erythropoietin
- myeloid growth factors
- platelet growth factor

30

hirudin

direct thrombin inhibitor

31

bivalirudin

direct thrombin inhibitor

32

Used to stop bleeding due to heparin

PROTAMINE

33

Enoxaparin: MOA, Advantages, A/E

LMWH

- selectively inhibit Xa, less effect on thrombin
- given subcutaneously

advantages:
- less hemorrhagic complication, less thrombocytopenia
- equally efficacious
- increased bioavailability
- less frequent dosing, bc longer half life
- less effect on aPTT

A/E: BLEEDING!
- close monitoring of activated partial thromboplastin time (aPTT)
- PROTAMINE is used to stop bleeding due to heparin
- Moderate & transient thrombocytopenia --> immune mediated
- Osteoporosis on prolonged use

34

Direct Thrombin Inhibitors: names & MOA

Lepuridin
bivalirudin
argatroban

- directly bind to thrombin and inhibits the downstream effects
- obtained from proteins made by medicinal leech

35

Warfarin MOA

- decrease hepatic synthesis of Vit K dependent clotting factors: Prothrombin, VII, IX, X
- by preventing the gamma carboxylation of glutamine residues of clotting factors

- this is done by inhibiting Vitamin K Epoxide Reductase--> which prevents the regeneration of hydroquinone form of Vit K

36

Dalteparin: MOA, Advantages, A/E

LMWH

- selectively inhibit Xa, less effect on thrombin
- given subcutaneously

advantages:
- less hemorrhagic complication, less thrombocytopenia
- equally efficacious
- increased bioavailability
- less frequent dosing, bc longer half life
- less effect on aPTT

A/E: BLEEDING!
- close monitoring of activated partial thromboplastin time (aPTT)
- PROTAMINE is used to stop bleeding due to heparin
- Moderate & transient thrombocytopenia --> immune mediated
- Osteoporosis on prolonged use

37

Lepuridin

Direct Thrombin Inhibitor
- directly bind to thrombin and inhibits the downstream effects
- obtained from proteins made by medicinal leech

Uses: alternative to heparin in heparin-induced thrombocytopenia

38

Warfarin A/E

1. Bleeding: ecchymosis, epistaxis, hematuria
- monitor, prothrombin time
- treatment: stop the drug, Vitamin K1, fresh frozen plasma

2. Skin Necrosis: rare complication seen during first week of therapy with warfarin
- due to reduced protein c synthesis
- manifests as dermal necrosis of extremities or breast

39

Tinzaparin: MOA, Advantages, A/E

LMWH

- selectively inhibit Xa, less effect on thrombin
- given subcutaneously

advantages:
- less hemorrhagic complication, less thrombocytopenia
- equally efficacious
- increased bioavailability
- less frequent dosing, bc longer half life
- less effect on aPTT

A/E: BLEEDING!
- close monitoring of activated partial thromboplastin time (aPTT)
- PROTAMINE is used to stop bleeding due to heparin
- Moderate & transient thrombocytopenia --> immune mediated
- Osteoporosis on prolonged use

40

Uses of Heparin

used when anticoagulation is required immediately (rapid anticoagulation)
- DVT
- PE
- AMI
- coronary angioplasty along with fibrinolytic
- anticoagulant of choice during pregnancy*
- Atrial fibrillation
- cerebrovascular disease
- vascular surgery
- prosthetic heart valves

41

alternatives to heparin in heparin-induced thrombocytopenia

- Lepuridin
- argatroban

42

Bivalirudin

Direct Thrombin Inhibitor
- directly bind to thrombin and inhibits the downstream effects
- obtained from proteins made by medicinal leech

Uses: used in combination with aspirin during angioplasty

43

Phytonadione

Preparation of Vitamin K1
- given orally
- Vitamin K is a Cofactor for synthesis of clotting factors Prothrombin, factor VII, IX and X

44

Factors increasing Iron absorption

- acid
- ascorbic acid
- aminoacids
- meat

45

Argatroban

Direct Thrombin Inhibitor
- directly bind to thrombin and inhibits the downstream effects
- obtained from proteins made by medicinal leech

Uses: alternative to heparin in heparin-induced thrombocytopenia

46

Warfarin Pharmacokinetics

Inhibits synthesis of clotting factors by liver but doesn't affect clotting factors that's already made!

- given orally --> onset of action delayed
- highly bound to plasma proteins (99%)
- crosses placenta --> can cause hemorrhagic disorder, bone defects in fetus
- monitored by INR (international normalized ratio)
- recommended INR = 2-3

INR = test prothrombin time / control prothrombin time

47

Warfarin Uses

same as heparin
- used for long-term anticoagulation; FOR MAINTENANCE!
- DVT, PE
- AMI
- Coronary angioplasty along with fibrinolytics
- NOT anticoagulant of choice during pregnancy!!!!!
- Atrial fibrillation
- Cardiovascular disease
- vascular surgery
- prosthetic heart valves

48

filgrastim

granulocyte colony stimulating factor (G-CSF)

49

Vitamin K

Cofactor for synthesis of clotting factors Prothrombin, factor VII, IX and X
- preparation: phytonadione (Vit K1)
- given orally

Uses:
- obstructive juandice, liver disease
- malabsorption syndromes
- newborns (premature Vit K1 mg IM)
- overdose of oral anticoagulants

50

Which form of iron is absorbed?

Fe2+ (ferrous)
- max absorption in duodenum

Fe3+ = ferric iron

51

Oral iron preparations: types & A/E

- ferrous sulfate
- ferrous gluconate
- ferrous fumerate

A/E:
- Epigastric pain
- constipation
- metallic taste
- nausea, vomiting
- staining of teeth

52

Factors decreasing Iron absorption

- antacids
- phosphates
- phytates
- tetracyclines
- presence of food

53

- Vomiting, hematemesis, bloody diarrhea followed by shock,
- severe metabolic acidosis, coma and death

acute iron poisoning

- common in infants and children

Treatment: Deferrioxamine: iron chelating agent

54

parenteral iron: names, indications for use, and uses

- iron dextran (IV/IM)
- sodium ferric gluconate complex (only IV)
- iron sucrose (only IV)

indications for use:
- oral iron not tolerated
- severe deficiency
- malabsorption
- non-compliance

Uses:
1. iron deficiency anemia
- nutritional deficiency (premature infants, growing children)
- anemia of pregnancy
- blood loss (GI bleeding)
- malabsorption

2. pregnant and lactating women -- prophylaxis

55

Cyanocobalamine

Vitamin B12 Preparation

Absorption: intrinsic factor (gastric parietal cell) + Vit B12 --> absorbed in distal ileum

Uses: megaloblastic anemia and pernicious anemia

56

sargramostim

granulocyte/macrophage colony stimulating factor (CM-CSF)

57

Folic Acid

Folic acid --Folic reductase (enzyme)--> dihydrofolic acid --dihydrofolate reductase (enzyme)--> tetrahydrofolic acid

dihydrofolate reductase (enzyme) is inhibited by methotrexate

Uses: megaloblastic anemia caused by
a) nutritional deficiency, alcoholics, liver diseases
b) pregnancy, malabsorption
d) pregnancy--maternal FA deficiency, associated with neural tube defects (i.e. spinabifida)
c) drugs:
- phenytoin: antiepileptic
- sulfonamides: treat malaria, antibacterial (in high [ ] --> anemia)
- methotrexate: anti-cancer drug
- INH: tx malaria
- OCP

Methotrexate toxicity:
- leucovorin (aka folinic acid = active form of folic acid)/citrovorum factor/folinic acid
- Mtx-DHFR inhibitor (FA is not effective)

Leucovorin rescue: giving leucovorin when used to give high dose of methotrexate because rescuing bone marrow cells

58

Hydroxyocobalamine

Vitamin B12 Preparation

Absorption: intrinsic factor (gastric parietal cell) + Vit B12 --> absorbed in distal ileum

Uses: megaloblastic anemia and pernicious anemia

59

Acute Iron Poisoning

- common in infants and children

Symptoms:
- Vomiting, hematemesis
- bloody diarrhea followed by shock
- severe metabolic acidosis, coma and death

Treatment: Deferrioxamine: iron chelating agent

60

Hemopoietic growth factors

recombinant human erythropoietin:
- erythropoitin
- darbopoietin

- colony stimulating factors: G-CSF and GM-CSF

Uses:
- anaemic of chronic renal failure (because doesn't form enough EPO --> anemia)
- cancer chemo induced anemia
- anemia in AIDS patients--Zidovudine--> causes BM suppression

61

Myeloid Growth Factors

promote WBC
- granulocyte colony stimulating factor (G-CSF) -->filgrastim
- granulocyte/macrophage colony stimulating factor (CM-CSF)-->sargramostim

Use: to treat neutropenia with anticancer drugs & zidovudine

62

Megakaryocytic Growth Factors

Interleukin 11 (oprelvekin)
- stimulate the formation of megakaryocytic and increase their number in peripheral blood

Use: thrombocytopenia after a cycle of cancer chemotherapy

63

Deferrioxamine

iron chelating agent
- used to treat acute iron poisoning

64

Which anticoagulant has a delayed onset?

Warfarin

Heparin has an immediate onset