M2-C5-L34 --> Anticoagulants

Front 1

ANTI-COAGULATION DRUGS
OVERVIEW

- list the 3 categories of Anti-coagulation Drugs

Back 1

(THC)

- Thrombolytics (direct-acting)

- Heparin + heparin derivatives

- Coumarins (i.e. - Warfarin)

Front 2

WARFARIN

- Warfarin is what kind of derivative?

Back 2

- Coumarin derivative

Front 3

WARFARIN

- Interferes with the _____ process of the ______ dependent clotting factors at the _______ location.

Back 3

- Synthesis

- Vitamin K

- Liver

Front 4

WARFARIN

- Liver synthesizes what Vitamin K dependent Coagulation factors. x4

- Liver synthesizes what Vitamin K dependent ANTI-coagulation proteins? x3

Back 4

- Factor II (2)
- Factor VII (7)
- Factor IX (9)
- Factor X (10)

- Factor C
- Factor S
- Factor Z

Front 5

WARFARIN

- Vit. K dependent clotting factors undergo what reaction TYPE at the liver?

- what Enzyme does this?

Back 5

- Glutamate Carboxylation

- GGCX
(Gamma Glutamyl CarboXylase)

Front 6

WARFARIN

- What are the Reactants (x2) in the Vit. K dependent clotting factor reaction?

- What are the Products? (x2)

Back 6

- Prothrombin Precursor
- Reduced Vit. K

- Prothromin
- Oxidized Vit. K

Front 7

WARFARIN

- For the Vit. K dependent clotting factor reaction, what is the other essential LINKING reaction?

- what TYPE of reaction is this?
- Enzyme responsible?

Back 7

- "REcycling" or REducing of Oxidized Vitamin K

- Reduction

- VKORC1
(Vit. K epOxide Reductase Complex 1)

Front 8

WARFARIN

- For "REcycling" Vit. K, what is the reactant?

- Product?

- Enzyme?

- Describe the molecular change

Back 8

- Oxidized Vit. K

- Reduced Vit. K

- VKORC1

- KO (oxid. VK) --> KH2 (red. VK)

Front 9

WARFARIN

- in the Vit. K dependent clotting factor reaction, describe the chemical change seen for both both products.

Back 9

1.) Glutamic acid (precursor)
--> gamma-Carboxyglutamic acid (Prothrombin)

2.) KH2 (red. Vit. K) --> KO (oxid. vit. K)

Front 10

WARFARIN

- What is Factor II?
- What is Factor IIa?
- What is Factor I?
- What is Factor Ia?

- Warfarin causes the reduced levels of what Factor?

Back 10

- Prothrombin (activated by V, becomes)
- Thrombin (will activate -->)
- Fibrinogen (which becomes)
- Fibrin

- Prothrombin

Front 11

WARFARIN

- Warfarin inhibits which enzyme?

- so direct accumulation of?
- and reduced levels of?

Back 11

- VKORC1
(Vit. K epOxide Reductase Complex 1)

- Oxidized Vitamin K
- Reduced Vitamin K

Front 12

WARFARIN

- why is Vitamin K in its Reduced form so important?

Back 12

- Vit. K is the CoFactor of GGCX

and

the reduced form is the only form accepted by GGCX

Front 13

Back 13

Front 14

WARFARIN

- Administration?
- Absorption?

Back 14

- PO

- Rapid & Complete

Front 15

WARFARIN

- Distribution?
- Vd value?

Back 15

- Plasma protein binding = 99%

- small

Front 16

WARFARIN

- Metabolism by?
- Half life?

Back 16

- Hepatic CYP2 C9

- 40 hours

Front 17

WARFARIN

- Onset?
- Duration?

Back 17

- 2 to 3 days

- 2 to 5 days

Front 18

WARFARIN

- what are the major side effects?

Back 18

(WAR is broadcast by the BBC)

- Bleeding
- Birth Defects
- Cutaneous necrosis

Front 19

WARFARIN

- out of the Major side effect, which is the MAIN concern?

- what can be given to combat this Major Side Effect? x3

Back 19

- Bleeding

- Vitamin K
- Clotting Factors
- Fresh Frozen Plasma

Front 20

WARFARIN

- why is Warfarin contraindicated in pregnant women?

- Warfarin is teratogenic during what weeks of pregnancy?

Back 20

- Crosses the Placenta

- weeks 6 to 12

Front 21

WARFARIN

- if given to pregnant chick, compare the drug concentrations in mom vs. fetus.

Back 21

- [maternal] = [fetus]

Front 22

WARFARIN

T/F : Warfarin is found breast milk

T/F : Other Coumadins are found in breast milk.

Back 22

- False
(Warfarin is NOT found in breast milk)

- True
(other Coumadins are found in breast milk)

Front 23

WARFARIN

- list some non-major side effects x7

Back 23

(DA FAUNA)

- Dermatitis
- Abdominal cramps

- Fever
- Alopecia
- Urticaria
- N/V/D
- Anorexia

Front 24

DRUG INTERACTIONS

- when administering another drug with Warfarin, what type of monitoring is necessary?

Back 24

- Prothrombin time (PT)

Front 25

DRUG INTERACTIONS

With Warfarin, an INCREASED Anti-Coagulation would occur when mixing with drugs that:

- Displace.........

- Increase........
- Decrease.........

- Inhibit........... x2

Back 25

- Displace Plasma Protein bound Warfarin

- Increase the Affinity of the Warfarin "receptor site"

- Decrease the Bioavailability of Vitamin K

- Inhibit the Liver Microsomal Enzyme System

- Inhibit the Platelet Function

Front 26

DRUG INTERACTIONS

With Warfarin, a DECREASED Anti-Coagulation would occur when mixing with drugs that:

- Stimulate........... x2

- Inhibit...........

Back 26

- Stimulate the Liver Microsomal Enzyme System

- Stimulate the Clotting Factor synthesis

- Inhibition of Absorption

Front 27

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Displace Plasma Protein bound Warfarin, will have what effect on Anti-coagulation?

- why?

- drug example that does this

Back 27

- Increase Anti-coagulation

- b/c of the high degree of Warfarin bound to proteins, even a small decrease in the amount bound can lead to significant increase in free active drug levels

- Salicylates such as ASA

Front 28

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Inhibit Liver Microsomal Enzyme System will have what effect on Anti-coagulation?

- why?

- drug example that does this

Back 28

- Increase Anti-Coagulation

- Decreased metabolism will lead to increased Bioavailabiity of Warfarin

- Quinidine

Front 29

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Increase the Warfarin "Receptor site" affinity, will have what effect on Anti-coagulation?

- why?

- drug example that does this

Back 29

- Increase Anti-Coagulation

- Increased Efficacy of Warfarin at given plasma levels

- d-Thyroxine

Front 30

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Stimulate the Liver Microsomal Enzyme System, will have what effect on Anti-coagulation?

- why?

- drug example that does this

Back 30

- Decreases Anti-coagulation

- Decreases plasma half-life of Warfarin

- Barbiturates

Front 31

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Stimulate Clotting Factor synthesis, will have what effect on Anti-coagulation?

- why?

- drug example that does this? x2

Back 31

- Decrease Anti-Coagulation

- Antagonizes Warfarin activity

- Vitamin K
- Estrogens

Front 32

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Reduce the Availability of Vitamin K, will have what effect on Anti-coagulation?

- drug example that does this? x2

Back 32

- Increase Anti-Coagulation

- Broad Spectrum Antibiotics
- Laxatives

Front 33

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Inhibit platelet functioning, will have what effect on Anti-coagulation?

- drug example that does this

Back 33

- Increase Anti-Coagulation

- ASA

Front 34

DRUG INTERACTIONS

- Mixing Warfarin with drugs that Inhibit Absorption, will have what effect on Anti-coagulation?

- drug example that does this

Back 34

- Decrease Anti-Coagulation

- Cholestyramine

Front 35

DRUG INTERACTIONS

Warfarin + d-Thyroxine = ?

why?

Back 35

- Increases Anti-coagulation

- D-thyroxine increases the Affinity of warfarin receptor sites, thus increasing efficacy at a given plasma level

Front 36

DRUG INTERACTIONS

Warfarin + ASA = ?

why?

Back 36

- Increase Anti-Coagulation

- Displaces Plasma Protein bound Warfarin

- Inhibits Platelet functioning

Front 37

DRUG INTERACTIONS

Warfarin + Quinidine = ?

why?

Back 37

- Increases Anti-Coagulation

- Quinidine Inhibits Liver Microsomal Enzyme system

Front 38

DRUG INTERACTIONS

Warfarin + Broad Spectrum Ab = ?

why?

Back 38

- Increased Anti-Coagulation

- Decreases the Vitamin K bioavailability

Front 39

DRUG INTERACTIONS

Warfarin + Laxatives = ?

why?

Back 39

- Increases the Anti-coagulation

- Reduces the Vitamin K bioavailability

Front 40

DRUG INTERACTIONS

Warfarin + Barbiturates = ?

why?

Back 40

- Decreases the Anti-coagulation

- Barbiturates Stimulate the Liver Microsomal Enzyme system. Thus decreasing warfarin half life.

Front 41

DRUG INTERACTIONS

Warfarin + Vitamin K= ?

why?

Back 41

- Decreases the Anti-coagulation

- antagonizes warfarin activity

Front 42

DRUG INTERACTIONS

Warfarin + Estrogens = ?

why?

Back 42

- Decreases the Anti-coagulation

- antagonizes warfarin activity

Front 43

DRUG INTERACTIONS

Warfarin + Cholestyramine = ?

why?

Back 43

- Decreases the Anti-coagulation

- Inhibits absorption

Front 44

WARFARIN TIDBITS

- Warfarin would affect what lab test and how?

- why so?

Back 44

- Prolonged PT

- due to deficiency in Factor SEVEN

(PTT stays fine cuz factor 12 don't change nun)

Front 45

WARFARIN TIDBITS

- why would Warfarin cause cutaneous necrosis?

Back 45

- results from microvascular thrombosis caused by Deficiency in Vitamin K dependent ANTI-coagulant proteins C & S.

(think "C" for "C"utaneous necrosis)

Front 46

HEPARIN

- describe its Molecular Weight

- describe its structure

- where are Heparin found?

Back 46

2 to 40 kDa

N- & O- sulfated sugars
polymerized
by
glycoside bonds

Secretory granules of Mast Cells

Front 47

HEPARIN

- which Heparins possess most of the biological activity?

Back 47

- Lower MW polymers of Heparin

Front 48

HEPARIN

- describe the activity of heparin in vitro vs. in vivo

- describe its acidity

- describe its absorbance following PO

Back 48

- Active in vitro and in vivo

- most acidic organic acid in the body

- NOT absorbed following oral administration

Front 49

HEPARIN

- Heparin forms a complex by binding to what enzyme?

- this combined complex can then bind to what?
(thus forming what complex?)

- what is the end enzymatic effect?

- thus the enzymatic effects of Heparin affects coagulation how?

Back 49

- Binds & Activates AT III
(Anti-Thrombin III)

- Serine Protease
(forming the ternary complex)

- Serine Protease is inhibited

- Accelerates the Inactivation of Clotting Factors IIa (2a), Xa (10a), IXa (9a), XIa (11a), XIIa (12a)

Front 50

HEPARIN

- what type of enzyme is AT III?

- AT III is endogenous or exogenous?

- AT III inactivates what clotting factors? x5

- is this inactivation reversible or irreversible?

Back 50

- Serine Protease Inhibitor
(when activated by Heparin)

- AT III is Endogenous

- Factors IIa (2a), Xa (10a), IXa (9a), XIa (11a), XIIa (12a)

- Irreversible

Front 51

HEPARIN

- what unique sequence of Heparin binds to AT III with high affinity

- what F(x)'al group in the above sequence is required in binding?

- what is also required for UNFRACTIONATED Heparin

- what about for LOW MOLECULAR WEIGHT Heparin (LMWH)

Back 51

- PENTA-saccharide sequence

- Sulfate groups (-SO3-)

- Polysaccharide of at least 18 units is required

- 5 units for LMWH

Front 52

UNFRACTIONATED HEPARIN
Explain what is going on here.

Back 52

1.) AT III + Heparin

2.) Activated AT III will bind to Serine Protease

3.) Formation of Ternary complex

4.) Inactive Serine Protease bound to AT III

5.) Heparin released from the Ternary complex is free to bind and activate other AT III

Front 53

LOW MOLECULAR WEIGHT HEPARIN

- MW?

- LMWH-AT III complex Preferentially binds to?

Back 53

- 4,000 Dalton to 6,000 Dalton

- Factor Xa (10a)
(via AT III & not the LMWH)

Front 54

LOW MOLECULAR WEIGHT HEPARIN

- compare half life vs unfractionated Heparin

- compare side effects vs unfractionated Heparin

Back 54

- double the half life

- less bleeding

Front 55

LOW MOLECULAR WEIGHT HEPARIN

- LMWH has Less Effect on what Anti-coagulation processes when compared to Unfractionated Heparin. x2

Back 55

- Less Effect on Platelet Activation

- Less Effect on Factor XIII (13) Activation

Front 56

UNFRACTIONATED HEPARIN

- monosaccharide units?
- binding components?

LOW MOLECULAR WEIGHT HEPARIN

- monosaccharide units?
- binding components?

Back 56

UNFRACTIONATED HEPARIN
>= 18 monosaccharide units
Heparin binds ATIII & Factor IIa (2a)
Factor IIa (2a) also binds to AT III

LMWH
< 18 monosaccharide units (minimum 5 required)
LMWH binds to AT III only
Factor Xa (10a) binds to AT III only (& not LMWH)

Front 57

HEPARIN PHARMACOKINETICS

- administration

- distribution

Back 57

- IV or SubQ
(no oral absorption)

- Vd is small due to extensive binding

Front 58

HEPARIN PHARMACOKINETICS

- onset for IV

- onset SubQ

- Duration

Back 58

- immediate

- 20 to 60 minutes

- less than 2 hours

Front 59

HEPARIN SIDE EFFECTS

- what is the main concern

- what is the antidote

Back 59

- Bleeding

- Protamine Sulfate

Front 60

HEPARIN SIDE EFFECTS

- 1% to 5% of Heparin patients suffers from what condition?

- results from the formation of what?

- the complex formed above will bind to what?

- above binding will lead to inappropriate formation of?

Back 60

Rapid & Profound Thrombocytopenia
(w/ paradoxical arterial or venous thrombosis)

- Ab directed against platelet Factor IV (4) complexed w/ Heparin

- Heparin-Ab complex binds to Platelets

- Aggregation & Thrombous formation

Front 61

HEPARIN SIDE EFFECTS

- patients on Heparin for 6 months may suffer from?

- usually accompanied with how much dosage?

Back 61

- Reversible Osteoporosis

- 6 months therapy w/ >15,000 U/day

Front 62

What type of Heparin is this?
# of Monosaccharide units?

Back 62

LMWH
< 18 monosaccharide units

Front 63

What kind of Heparin is this?
# of monosaccharide units?

Back 63

Unfractionated Heparin
> than 18 monosaccharide units

Front 64

ANTI-PLATELET DRUGS

- list 3 anti-platelet drugs

Back 64

- ASA

- Clopidogrel

- Glycoprotein IIb / IIIa inhibitors

Front 65

ASPIRIN

- MOA will Inactivate?

- via what reaction?

- Irreversible or Reversible

Back 65

- inactivates Cyclooxygenase
by
- Covalent Acetylation
is
- Irreversible

Front 66

ASPIRIN

- ASA inhibits what Constitutively?

- ASA inhibits what in Induced way?

Back 66

- COX-1
(prostaglandin G/H synthase 1)

- COX-2
(prostaglandin G/H synthase 2)

Front 67

ASPIRIN

- ASA inhibition of COX will lead to the inhibition of what important Platelet Aggregator?

Back 67

- Thromboxane A2

(TxA2)

Front 68

ASPIRIN

- Selectivity of ASA occurs for COX where?

Back 68

- Platelet COX

Front 69

ASPIRIN

- Platelet COX is ______ in the ______ circulation

BEFORE or AFTER

- ASA is ________ in the _____

Back 69

- Acetylated
- Portal Circulation

BEFORE

- Deacylated
- Liver

Front 70

ASPIRIN

- the selectivity of ASA for platelet COX means that the Systemic Vasculature is unaffected because?

Back 70

- Platelets are NOT affected by Salicylate

Front 71

ASPIRIN PHARMACOKINETICS

- Absorption

- Distribution in Low doses

- Distribution in High doses

Back 71

- 70%

- mostly bound to plasma protein

- smaller % is plasma protein bound
(thus more available to tissues)

Front 72

ASPIRIN PHARMACOKINETICS

- Elimination by what? and what %?

- what is excreted and how?

Back 72

- Hepatic Metabolites (75%)

- Parental compound excreted
- via Urine

Front 73

ASPIRIN PHARMACOKINETICS

- Onset?

- Duration?

Back 73

- 30 minutes

- 7 to 10 days

Front 74

ASA ADVERSE ACTIONS

- primarily occurs in what system?

- give 3 examples of major side effects

- list other minor side effects x5

Back 74

- GI

- Epigastric pain (heartburn, nausea)
- GI blood loss
- Gastric Ulcers

(GRANT)
- Gout
- Rash
- Acid-base disturbance
- Nasal polyps
- Tinnitus

Front 75

ASPIRIN INTERACTIONS

- Decreases the effectiveness of what drugs?

- though usually not a problem if?

Back 75

- Anti-Hypertensives

- with Low doses, not a problem

Front 76

ASPIRIN INTERACTIONS

- Increases the effects of what drug?

Back 76

- Warfarin

Front 77

ASPIRIN INTERACTIONS

- Attenuates the actions of what drugs?

- give example

Back 77

- Uricosuric agents

- Probenecid

Front 78

OTHER ANTI-PLATELETS

- list 2 other Anti-platelet drugs

- what is their MOA?

- thus, the MOA will have what effect on cAMP?

Back 78

- Ticlopidine
- Clopidogrel

- P2Y2 Purine Receptor Antagonists

- Increase cAMP
(thus decrease aggregation)

Front 79

TICLOPIDINE & CLOPIDOGREL

- will reduce the incidence of? x2

- currently the drug of choice in? x2

- particularly effective when combined with?

Back 79

- MI
- CVA

- Prophylaxis of Subacute Stent Thrombosis
- Post-Ischemic Stroke Tx

- ASA

Front 80

GLYCOPROTEIN IIb/IIIa INHIBITORS

- list 3

Back 80

- Abciximab

- Tirofiban

- Eptifibatide

Front 81

GLYCOPROTEIN IIb/IIIa INHIBITORS

- what type of compound is Abciximab?

- Tirofiban?

- Eptifibatide?

Back 81

- Fab fragment
(directed to GP IIb/IIIa receptor)

- NonPeptide Inhibitor
(of GP IIb/IIIa receptor)

- Cyclic Peptide
(GP IIb/IIIa receptor antagonist)

Front 82

FIBRINOLYTICS

- restores blood flow to an Injured area by ....?

Back 82

- lysing Thrombus into Soluble Fibrin Degradation products

Front 83

FIBRINOLYTICS

- give 4 examples

Back 83

(Alt USA)

- Alteplase (rtPA)

- Urokinase
- Streptokinase
- Anistreplase

Front 84

FIBRINOLYTICS

- MOA?

Back 84

- accelerates the conversion of Plasminogen to Plasmin

Front 85

FIBRINOLYTICS

- Plasmin is what type of enzyme?

- functionally does what?

Back 85

- Protease

- Breaks down Fibrinogen & Fibrin into degradation products

Front 86

FIBRINOLYTICS

- the major M&M of ThromboEmbolic Dz is due to?

- thus leading to?

Back 86

- Vascular occlusion

- Ischemia & Infarction

Front 87

FIBRINOLYTICS

- what is the purpose and Tx goal?

Back 87

- Rapid Reperfusion of Infarcted area preserves more tissue.

Front 88

FIBRINOLYTICS

- Fibrinolytic success is Dependent upon what?

Back 88

- Time lapse btw onset of Sx & administration of fibrinolytic

Front 89

FIBRINOLYTICS

Time Lapse btw Sx onset & Fibrinolytic administration for:
- DVT?
- PE?
- MI
- CVA (stroke)?

Back 89

DVT: <= 7 days

PE: <= 2 days

MI: 2 to 4 hours

Stroke : < 3 hours

Front 90

FIBRINOLYTICS

- Major side effect?

Back 90

- Bleeding