Drugs that Affect Coagulation: Lecture Objectives. Fitzakerley. 05. 07. 09. Katelyn Rogers
1. Be able to diagram the coagulation & fibrinolytic pathways, including the interaction of protein C w/ those
pathways (Sketch on separate sheet). Define how pro- & anti-coagulant drugs (including thrombolytics & antiplatelet drugs) interact w/ specific clotting factors & naturally occurring molecules in these pathways. (On sketch
label where the drugs interact w/ the factors)
2. Be able to identify both the common & the distinguishing characteristics of thrombolytic agents. Describe the
similarities & differences btwn streptokinase/urokinase & tPAs.
Common characteristics of thrombolytic agents:
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Dissolve clots
Process of changing/moving plasmin so it
can be active
Given IV
Short activation & t ½
Used for recent MI (6hrs), PE, & DVT
Distinguishing characteristics of thrombolytic agents:
STREPTOKINASE:
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If patient is allergic to STREPTOKINASE use UROKINASE a
human kidney enzyme that converts
plasminogenplasmin, which has only fever & no
anaphylaxis for adverse effects.
Common contraindications/Precautions of
thrombolytic agents:
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Cause bleeding/hemorrhage
Therefore, don’t administer post-surgery,
post-trauma, hemorrhagic strokes,
pregnancy, or GI bleed/ulcer
Contraindicated w/ hypertension
Mech of action: not intrinsically active, causes a
conformational Δ in plasminogen exposing active site.
Adverse effects: isolated from bacteria, allergic rxn
includes anaphylaxis & fever.
tPAs (human melanoma cells): ALTEPLASE (unmodfd),
RETEPLASE (deleted some aas), TENECTEPLASE (substituted):
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Mech of action: selective activation of fibrin bound
plasminogen (easy target).
Only fibrinolytics approved for use in non-hemorrhagic
stroke (3hrs).
3. Compare & contrast: Green means good things. With respect to mechanism of action, pharmacokinetics (esp.
time to onset of activity), method of monitoring, antidotes, use during pregnancy & side effects.
a. Heparin & low molecular weight heparins
HEPARIN
LMWHs: DALTEPARIN &
ENOXAPARIN
Size (MW)
Big
Small
Anti-thrombin (Anti-IIa)
High
Low
Anti-Xa
Low
High
Bioavailability
Low
High
T1/2 (leading to ↓ dosing)
Shorter
Longer
Predictability
Poor
Good
Platelet inhibition
More
Less
Plasma protein bound
More
Less-not displaced as easily
HIT
More
Less
Monitor
All the time
Only during pregnancy
Antidote (PROTAMINE
High
Low
SULFATE) efficiency
b. Heparin & direct thrombin inhibitors (DTIs) & Warfarin.
HEPARIN
Mech of action
Pharmacokinetics
*time of onset
Requires AT III
binding (IIa,VIIa,IXa,
Xa, XIa, XIIa) & coats
bv wall ↓ platelet
binding & ↑
permeabilization.
IV or SC
*RAPID onset
Liver metabolism
Kidney excretion
DTIs: ARGATROBAN,
BIVALIRUDIN, HIRUDIN,
LEPIRUDIN
Interact directly w/
thrombin (IIa)
RUDINs- irreversible
ARGATROBAN- comp
antagonist
WARFARIN
IV
RUDINs- kidney excretion
ARGATROBAN- liver
metabolism
Oral
*RAPID onset
Narrow TI
99% bound to plasma proteins (easily
displaced)
S form (CYP2C) active- other drugs
affect it
R form (CYP1A2, 2C19, 3A4)- affects
other drugs
Gene modifications can affect
metabolism
Slow CYP2C9- ↑ serum conc
Resistant VKOR-↓ effectiveness
Coag cascade also resistance (Fact V
Leid)- -↓ effectiveness
No in vitro effect
INR- correlates w/ factor II.
Protein C & Factor VII deplete first,
causes coagulation temporarily.
Last is factor II (prothrombin).
PHYTONADIONE (Vitamin K)
Monitoring method
Frequent aPTT
Sometimes aPTT
ARGATROBAN- ↑es INR,
therefore can’t be used.
Antidotes
PROTAMINE SULFATE
NONE- irreversible, except
ARGATROBAN is
reversible, but no agents
exist
Use during pregnancy
Yes- doesn’t cross
placenta
Bleeding,
hypersensitivity which
can progress to
anaphylaxis, HIT.
Prolonged exposure:
osteoporosis, ↓ed AT
III leading to ↑ed
clotting, & a
mineracorticoid
defiency bc of ↓
aldosterone.
HEPARIN for immed
DVT, PE, MI, etc
In combination w/
thrombolytics &
GPIIb/IIIa inhibitors for
angioplasty or stent
placement.
Side effects
Therapeutic Uses
Bleeding, anaphylaxis, Abproduction against
LEPIRUDIN, which ↓es
clearance by kidney- drug
stays active longer-↑
anticoagulation). NO HIT!
HIT, BIVALIRUDINangioplasty
Inhibits VKOR (epoxide reductase),
which normally regenerates vit K. ↓
synthesis of vit K dpd clotting factors II,
VII, IX, & X.
No- crosses placenta TRANSITION TO
HEPARIN.
DRUG-DRUG INTERACTIONS
Bleeding, flatulence/diarrhea,
cutaneous necrosis from ↓ prot C,
chondrodysplasia punctata & blood dxs
in fetus/kids.
Long term tx for DVT, for 2-6 mos
following MI, & atrial fibrillation. Also
rodenticides.
Know the properties of agents that can reverse the actions of heparin & warfarin.
Side note: Vit K is fat-soluble vit made by gut bacteria (K2). Synthesis of factors II, VII, IX, & X dpd on it. Also impt for bone
mineralization.
WARFARIN’S antidote is PHYTONADIONE (Vitamin K1- made by plants):
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Prevents hemorrhagic dxs in newborns
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Correct vit K deficiency in ICU patients or patients on many antibiotics
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Counteract an overdose of Warfarin
o PHYTONADIONE acts as an antagonist, promoting reestablishment of normal clotting factor activity.
o
Takes 6-24 hrs
HEPARIN’S antidote is PROTAMINE SULFATE:
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Highly basic peptide that combines ionically w/ HEPARIN.
Lasts 2 hrs.
Routinely done in surgery, can even act as an anticoagulant.
Anaphylaxis can occur in diabetic patients.
4. Understand how particular disease states &/or co-administration of other drugs alter the efficacy & side effects
of warfarin (esp. why it is the metabolism of S-warfarin that is critical). Be able to describe specific
pharmacokinetic & pharmacodynamic principles governing the interactions of warfarin, & be able to interpret
specific examples.
S-WARFARIN is the active form. Other drugs can affect the CYP2C9 of S-WARFARIN, while R-WARFARIN
(CYP1A2, 2C19, 3A4) affects other drugs. Most importantly, if other drugs increase the effects of S-WARFARIN,
we must be careful because of WARFARIN’S very low therapeutic index.
Drugs/dxs that increase effects of WARFARIN do so by:
 inhibition of CYP450 metabolism (acute alcohol, liver dx)
 decreased plasma protein binding (phenytoin initially)
 decreased platelet/clotting factor fxn (antiplatelet drugs, HEPARINs, DTIs)
 decreased availability of vit K (diarrhea, inadequate diet)
 polymorphism in CYP2C9  slower metabolism
Drugs/dxs that decrease effects of WARFARIN do so by:
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Induction of CYP450 metabolism (chronic alcohols, barbs, phenytoin ultimately)
Decreased absorption (cholestyramine)
Increased clotting factor/vit K conc (diuretics, hyperlipidemia, edema, hypothyroidism)
Genetic defects in coagulation cascade such as Factor V Leiden & mutations in VKOR  resistance to
WARFARIN
Drugs that ALWAYS interact w/ WARFARIN: aspirin, cimetidine, & phenytoin
5. Be able to use cytochrome p450 interaction tables to define drug-drug interactions (see the illustrative case on
the Web).
Inhibitors & substrates INCREASE the effectiveness of another drug metabolized by that same isozyme. Inducers
DECREASE effectiveness.
The ONLY affect of WARFARIN has on other drugs is to increase the plasma concentration bc neither SWARFARIN or R-WARFARIN are inducers or inhibitors of the CYP450 isozyme. Substrates can affect substrates
only (like the previous scenario w/ S&R-WARFARIN. Inducers & inhibitors affect drugs in substrate column.
Remember: all affect substrate.
Inhibitor
Inducer
Substrate
Substrates
Inhibitor
Inducer
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↑Substrate serum conc & efficacy
↑Substrate serum conc & efficacy
↓Substrate serum conc & efficacy
Many affects of drugs on WARFARIN:
 Substrates compete for binding sites increasing serum concs of both drugs (↓metabolism) leading to
increased efficacy. (This is how WARFARIN works)
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Case Online:
1 drug as an inhibitor, simply inhibits the isozyme (eg. Fluvoxamine inhibits CYP2C9 for eg) resulting in
increased serum substrate (S-WARFARIN) concentrations (↓ metabolism) leading to increased efficacy.
1 drug as an inducer, simply increases the activity of the isozyme (CYP2C9 for eg) resulting in decreased
serum concentrations of that drug (↑metabolism) leading to decreased efficacy, while increasing the other
drug serum concentrations (substrate: S-WARFARIN) thereby increasing its efficacy. – I am waiting for Dr.
Fitz response about this!
All three of these drugs are substrates, rather than inducers or inhibitors, of CYP450 isozymes:
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S-warfarin (the active ingredient) for CYP 2C9
R-warfarin for CYP 1A2, 2C19 and 3A4
metoprolol for CYP 2D6
amitryptylline for CYP 1A2, 2C19 and 2D6
So:
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Once physician changed to Fluvoxamine:
amitryptylline and metoprolol compete with each other for metabolism via 2D6
R-warfarin increases the efficacy of amitryptylline via competition for 1A2 and 2C19
(amitryptylline doesn't affect the efficacy of warfarin because R-warfarin is not the
active ingredient)
Presumably, these interactions have been managed in this patient by adjusting dosages of all 3
medications, as evidenced by the fact that she has been stable for several years
Once Paraxetine is added: Paroxetine is another substrate of CYP 2D6. Adding paroxetine
increases the circulating concentrations of amitryptylline and metoprolol by decreasing their
metabolism. Although amitryptylline is being given to this patient to manage her diabetic
neuropathy, it is also a sedating antidepressant.
Fluvoxamine is an extremely potent inhibitor of CYP 1A2
and 2C9, as well as 2C19 and 3A4.
The most critical drug interaction caused by the addition of
fluvoxamine is a decrease in the metabolism of S-warfarin
(2C9), which is reflected in the increase in the patient's INR.
The target range for INR is 2.5-3.5; a value of 5 means that
this patient has severely decreased clotting factor
concentrations, and is at risk for hemorrhage (actually, is
already hemorrhaging, as evidenced by the dark urine).
In addition, inhibition of 1A2 and 2C19 by fluvoxamine
means that the amitriptyline concentrations will remain
elevated (causing the sedation and dizziness), as well as
increasing R-warfarin concentrations which will exacerbate
the problems with amitriptyline
The drug interaction tables would predict, therefore, that adding paroxetine would increase the
side effects of amitryptylline, which include sedation and antimuscarinic effects (dry mouth,
dizziness).
6. Know the specifics of the anti-coagulant, fibrinolytic & anti-inflammatory actions of DROTECOGIN ALFA.
(USED IN DIC)
Anti-coagulant actions: ↓ Va & VIIIa therefore ↓thrombin formation, ↓platelet formation & TF expression.
Fibrinolytic actions: ↓TAFI & PAI-1 (both of which are inhibitors) allowing for ↑tPA (lysis of clot)
Anti-inflammatory actions:↓TNF, ↓neutrophil activation, &↓cytokines from macrophages
7. Be able to describe w/ the biochemical mechanisms of action & adverse effects of antiplatelet agents. Know the
specific instances where antiplatelet drugs are used in conjuction w/ other anti-clotting agents.
Mechanism of action:
Adverse Effects:
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ASPIRIN inhibits cyclooxygenase preventing PG synthesis.
ABCIXIMAB, EPTIFIBATIDE, & TIROFIBAN block Gp IIb/IIIa receptor
TICLOPIDINE & CLOPIDOGREL inhibit the binding fibrinogen to activated platelets by blocking the ADP
receptor.
DIPYRIDAMOLE inhibits cyclic nucleotide phosphodiesterase.
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(Ultimately, an inhibition of PDE33 - which is an inhibitor of cAMP2 - which normally inhibits degranulation1)
(↓granulation3 - ↑ granulation2 - ↓ granulation1)
1-first step, 2-second step, 3-third step
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ABCIXIMAB, EPTIFIBATIDE, & TIROFIBAN + HEPARIN & ASPIRIN: percutaneous
transluminal coronary angioplasty to prevent abrupt closure of vessel.
DIPYRIDAMOLE + WARFARIN: prevents embolization from prosthetic heart valves
ASPIRIN bleeding, ulcers, CNS,
tinnitus
ABCIXIMAB (hypersensitivity-TB),
EPTIFIBATIDE, & TIROFIBAN bleeding
& thrombocytopenia
TICLOPIDINE (most) &
CLOBPIDOGREL bleeding, diarrhea,
rash (10-15%); leucopenia (1%); &
thrombotic thrombocytopenia
purpura (<1%).
DIPYRIDAMOLE neglegible
8. Know the drugs & plasma fractions that are used specifically in the tx of vit K deficiency, factor VIII deficiencies
[classic hemophilia (hemophilia A); and von Willebrand’s disease] and factor IX deficiency (Christmas disease,
hemophilia B).
Deficiency/Dx
Vit K (newborns & ICU/multiple antibiotics patients)
Hemophilia A & von Willebrand’s dx (Factor VIII)
Hemophilia B, Christmas dx (Factor IX)
Drug/plasma fraction
PHYTONADONE
LYOPHILIZED Factor VIII, CRYOPRECIPITATE (Factor VIII
& vWf), & DESMOPRESSIN ACETATE (↑es Factor VIII in
mild cases)
(FACTOR IX)
9. Understand the mechanism of action of the fibrinolytic inhibitors aminocaproic acid & aprotinin.
AMINOCAPROIC ACID (EACA) inhibits plasminogen activation
(counteract tPAs)
APROTININ is a serine protease inhibitor of the plasmin-streptokinase complex, thereby preventing fibrinolysis.