Anticoagulants and

Thrombolytic Drugs
Suggested Reading
*CH 34 Drugs Used in
Disorders of Coagulation
Katzung (online)

Scott M. Rawls
scott.rawls@temple.edu
Department of Pharmacology
Center for Substance Abuse Research
Lewis Katz School of Medicine
Temple University
 Lecture Objectives
Explain mechanism of action of aspirin as it relates to inhibition of platelet
aggregation and why inhibition of cyclooxygenase I (COX-I) by low doses
of aspirin is an effective approach for reducing platelet aggregation.
Explain why ADP (P2Y12) receptor antagonism by inhibits platelet
aggregation and contrast mechanisms of action of clopidogrel with
ticagrelor.
Explain how abciximab, tirofiban, and eptifibatide inhibit glycoprotein
IIb/IIIa receptors to slow rate of platelet aggregation.
Explain why disruption of vitamin K function reduces rate of coagulation.
Contrast mechanisms of action of heparin and warfarin as related to their
anticoagulant effects.
Discuss mechanisms of action of direct thrombin inhibitors and compare
these drugs with heparin at the mechanistic and therapeutic levels. .
Explain why activation of plasminogen by tissue plasminogen activator
(tPA) reduces thrombosis through a process called fibrinolysis.
Antiplatelet, Anticoagulant, and Thrombolytic Drug List
Cyclooxygenase (COX) Inhibitor Aspirin
Clopidogrel (Plavix)
Adenosine Diphosphate (ADP) Ticlopidine (Ticlid)
Inhibitor Prasugrel
Antiplatelet Ticagrelor (Brilanta)
Drugs Abciximab
Glycoprotein IIB/IIIA Eptifibatide
Inhibitor Tirofiban
Phosphodiesterase-3 Cilostazol
Drugs used to Inhibitor Dipyridamole

Treat Thrombi Vitamin K Antagonists Warfarin

Heparin
Enoxaparin
Indirect
Anticoagulant Dalteparin
Drugs Thrombin Tinzeparin
Inhibitors Xabans
Dabigatran
Direct
Argatroban
Hirudin Alteplase
Bivalidurin Reteplase
Thrombolytic Streptokinase
Drugs Anistreplase
 Platelet Aggregation and Blood Coagulation
Factors which decrease rate
of platelet aggregation
PLATELET

Drugs which increase the activity

PGI2
of the PGI2 pathway and increase
Cyclic AMP
intracellular cyclic AMP levels will
decrease rate of platelet aggregation

PLATELET

Factors which accelerate rate of platelet

aggregation and facilitate coagulation
TXA2
ADP PLATELET Drugs which block the physiological
Thrombin actions of TXA2, ADP and thrombin will
PLATELET
Fibrinogen prevent platelet aggregation or blood
Calcium Ions coagulation
 Review of Substances Involved in Aggregation and Coagulation
Substance Function Effect on platelet
aggregation or
coagulation
ADP Binds to ADP receptors on platelets and causes
glycoprotein (GP IIB/ IIIA) receptors to change
their conformational shape and become active
TXA2 Stimulates ADP release and promotes platelet
(Thromboxane A2) aggregation by activating positive feedback loop

PGI2 Inhibits ADP release and opposes TXA2, effects

(Prostaglandin) that oppose the positive feedback loop
Fibrinogen Soluble protein that binds to platelet glycoprotein
receptors (GP IIB/ IIIA receptors) on two adjacent
platelets
Fibrin Insoluble plasma protein formed from fibrinogen
through enzymatic actions of thrombin
Thrombin Enzyme- catalyzes conversion of soluble
fibrinogen into insoluble fibrin
Anti-thrombin-III Inactivates thrombin and slows the rate of
formation of fibrin: is heparin site of action
Vitamin K Prothrombin cofactor involved in warfarin
Platelet Aggregation TXA2 and ADP released from
activated platelets activate additional
Mechanism platelets which are recruited for
ADP aggregation TXA2

ADP Enlarged Activated

ADP exocytosis Platelet
+ P2Y12 (ADP)
Receptor TXA2
TXA2
_ ADP
GRANULES + Synthetase
PGH2
_
COX-1
ATP cAMP Ca++ Arachidonic
Acid
PDE-3
AC
AMP
+ TXA2
PGI2 Receptor +
PGI2 Receptor
TXA2

Activated
Platelets
Endothelial Cells
Collagen
 Summary: Physiological Regulation of
Favors Aggregation
Platelet Aggregation Opposes Aggregation
*Platelets are activated when they bind to damaged
endothelial cells in injured vessel; activated platelet
converts membrane phospholipids into arachidonic
acid, which is subsequently converted into
prostaglandins and TXA2 by the enzymes
cyclooxygenase (COX) and thromboxane A2
synthetase.
*Membrane phospholipids are also converted into the
second messengers DAG and IP3 in activated
platelets which leads to an increase in intracellular
Ca++ ion concentration which, in turn, causes
exocytosis of granules containing ADP and
serotonin. ADP and serotonin in the extracellular
compartment then bind to receptors on nearby
platelets and make them sticky, an effect that favors
platelet aggregation.
*TXA2 is released from activated platelet and binds to
specific receptors on other resting platelets nearby;
TXA2 receptor activation further activates the
platelet and facilitates aggregation, recruitment,
*Prostacyclin (PGI2) is synthesized and
constitutively released by intact
endothelial cells in the undamaged
portion of the vessels; PGI2 opposes
TXA2 and acts as an inhibitor of
platelet aggregation and positive
feedback.
*PGI2 binds to PGI2 receptor on nearby
platelet and stimulates the
conversion of ATP into cAMP.
*The increase in intracellular cAMP
blocks the release of ADP and
serotonin, an effect that slows the
rate of platelet activation and the
rate of platelet aggregation.
 Antiplatelet Drugs
Drug Class Drugs Mechanism Administration Therapeutic Uses Adverse
of Route Effects
Antagonism

Cyclooxygenase Aspirin Irreversible Oral *Heart Attack (MI) *Bleeding

(COX-1) I Inhibitor (81 mg) *Stroke
Phosphodiesterase- Dipyridamole Reversible Oral *Pulmonary *Bleeding
3 Inhibitors Cilostazol Hypertension
*Stroke
*Intermittent
Claudication

Adenosine Clopidogrel Irreversible Oral *Heart Attack (MI) *Bleeding
Diphosphate (ADP) Ticlopidine and *Stroke *Neutropenia
(Purinergic P2Y12) Prasugrel Reversible *Stent
Receptor Ticagrelor Implantation
Antagonists

Glycoprotein Abciximab Reversible Parenteral *Angioplasty *Bleeding

IIB/IIIA Receptor Eptifibatide
Antagonists Tirofiban
Aspirin Mechanism of Action
Aspirin Mechanism TXA2 and ADP released from
activated platelets activate additional
platelets which are recruited for
ADP aggregation TXA2

Enlarged Activated
ADP exocytosis Platelet

TXA2
ADP
GRANULES +
PGH2
ASPIRIN COX-1
Ca++ Arachidonic
Acid

TXA2
+ Receptor
TXA2

Activated
Platelets
Endothelial Cells
Collagen
 Aspirin Mechanism of Action
Analgesic Drug

Anti-inflammatory Drug
4 Clinical
Uses Antipyretic Drug

Antiplatelet Drug

3 Questions about antiplatelet effect of aspirin?

1. Why is aspirin but not selective COX-2 inhibitors
(e.g., rofecoxib, celecoxib) effective?
2. Why is aspirin but not other nonselective COX
inhibitors (e.g., indomethacin) effective?
3. Why is a low dose of aspirin 81 mg found in baby
aspirin a more effective dose for antiplatelet effects?
 ACTIVATED ASPIRIN NORMAL
ENDOTHELIAL
PLATELET
MECHANISM CELL

ARACHIDONIC ACID ARACHIDONIC ACID

COX-1 ASPIRIN COX-1 COX-2
81 mg

TXA2 PGI2 TXA2 PGI2

TXA2 >>> PGI2

TXA2 < PGI2

Notes: Platelet is not a cell. It is a cell fragment, meaning that it lacks ability to synthesize proteins
(e.g. cyclooxygenase). Since aspirin irreversibly acetylates (inactivates) COX in a particular platelet,
that platelet is not able to make any more COX or produce additional TXA 2 and PGI2 for the duration
of its lifetime (9-12 days). This restores the balance between PGI 2 and TXA2 and reduces the rate of
aggregation and risk of thrombus formation. Although aspirin also blocks COX in the endothelial
cells, this block is eventually overcome because the cell can produce more COX enzyme.
 ACTIVATED Selective COX-2 NORMAL
ENDOTHELIAL
PLATELET
MECHANISM CELL

ARACHIDONIC ACID Celecoxib ARACHIDONIC ACID

COX-1 Rofecoxib COX-1 COX-2

TXA2 PGI2 TXA2 PGI2

TXA2 >>> PGI2

TXA2 < PGI2

Notes: COX-2 inhibitors (rofecoxib, celecoxib) can increase the risk of platelet aggregation
because they inhibit COX-2. COX-2 is expressed by the endothelial cells, but not by activated
platelets, and its activity is linked to the production of PGI2. Thus, blocking COX-2 in the
endothelial cell effectively reduces the local concentration of PGI2 and shifts the local balance
toward TXA2. This means TXA2 > PGI2 which increases risk of platelet aggregation.
Phosphodiesterase-3 (PDE-3)
Inhibitors

Dipyridamole and Cilostazol

Mechanisms of Action
Dipyridamole/ Cilostazol TXA2 and ADP released from
Mechanism activated platelets activate additional
platelets which are recruited for
ADP aggregation TXA2

Enlarged Activated
ADP exocytosis Platelet

TXA2
TXA2
_ ADP
GRANULES + Synthetase
PGH2

COX
ATP cAMP Ca++ Arachidonic
DIPYRIDAMOLE Acid
PDE-3
AC
CILOSTAZOL
AMP
+ TXA2
PGI2 Receptor +
PGI2 Receptor
TXA2

Activated
Platelets
Endothelial Cells
Collagen
 Antagonists of Adenosine Diphosphate
(ADP) Receptor (also called
Purinergic P2Y12 Receptor)

Irreversible Reversible
Antagonists Antagonist

Clopidogrel (Plavix) Ticagrelor (Brilanta)

Prasugrel
Ticlopidine
Clopidogrel/ Ticlopidine/ TXA2 and ADP released from
Prasugrel/ Ticagrelor activated platelets activate additional
platelets which are recruited for
Mechanism ADP
aggregation TXA2
CLOPIDOGREL
ADP TICLOPIDINE Enlarged Activated
ADP exocytosis Platelet
+ P2Y12 (ADP)
Receptor TXA2
TXA2
_ ADP
GRANULES
+ Synthetase
_ PGH2

COX
ATP cAMP Ca++ Arachidonic
Acid
PDE-3
AC
AMP
+ TXA2
PGI2 Receptor +
PGI2 Receptor
TXA2

Activated
Platelets
Endothelial Cells
Collagen
 Mechanism of Action of P2Y12 Antagonists
In the absence of drug therapy, ADP (along with
TXA2) is the centerpiece of the positive feedback
loop which facilitates platelet recruitment and
platelet aggregation, especially as it relates to the
eventual activation of GP IIB/IIIA receptors and
the conversion of fibrinogen into fibrin. In a
pathophysiological (disease) state, overproduction
of ADP can lead to excessive platelet aggregation
and thrombosis by the following mechanism.
ADP is released from activated platelets into
the extracellular space where it recognizes and
binds to ADP (P2Y12) receptors on adjacent
platelets.
P2Y12 receptor activation is negatively coupled
to cyclic AMP production. That is, P2Y12
receptor activation inhibits the production of
cyclic AMP.
The reduced levels of intracellular cyclic AMP
means that there is now less inhibition of
ADP and serotonin release. Thus, more and
more ADP continues to be released and
platelet aggregation is enhanced.
In the presence of drug therapy (clopidogrel,
ticlopidine, prasugrel, ticagrelor), the following
mechanism occurs:
The drugs bind to and block the P2Y12
receptor. Thus, ADP is now unable to bind to
and activate its receptor.
Because P2Y12 receptors are rendered inactive
by the drug blockade, intracellular cyclic
AMP production is NOT inhibited. Because
the intracellular cyclic AMP concentration is
either normalized or increased as a result of
the P2Y12 receptor block, further ADP and
serotonin release from the platelet is now
INHIBITED. This inhibition of ADP release
from the platelet slows the rate of platelet
activation particularly by preventing any
subsequent activation of GPIIB/IIIA receptors
and the rate of platelet aggregation.
Indications and Adverse Effects of
P2Y12 Antagonists
Indications
*Prevention of myocardial infarction and stroke
*Prevention of thrombosis after coronary stent
implantation (often given with aspirin)
*Most efficacious in smokers

Adverse Effects
(no antidote)
*Bleeding
*Neutropenia
*TTP (Thrombotic thrombocytopenic purpura)
*Pruritis (itch)
The old drug (Clopidogrel)
Clopidogrel versus
the new drug (Ticagrelor)
Ticagrelor
 New PY2Y12 Antagonist (Ticagrelor)
approved in July 2011
Variable Ticagrelor Clopidogrel
(Brilanta) (Plavix)
Site of Action P2Y12 (ADP) receptor P2Y12 (ADP) receptor

Mechanism of Reversible inhibition of P2Y12 Irreversible inhibition of

Action (ADP) receptor P2Y12 (ADP) receptor
Administration Oral Oral
Route
Onset of Action Faster Slower

Duration of Shorter Longer

Action
Adverse Effects Bleeding, skin rash, dyspnea Bleeding, neutropenia
Pharmacokinetics Efficacy not dependent on Prodrug efficacy
CYP2C19 activity dependent on CYP2C19
 Reversible GPIIB/IIIA Receptor Antagonists

Abciximab, Eptifibatide and

Tirofiban Mechanisms of Action
Glycoprotein (GP) Receptors (protein + carbohydrate
and involved in recognition and signaling)

GPIB
Platelet adhesion binds to
both circulating von willebrand
factor (VWF) and underlying
blood vessel). Links activated
platelets to vessel.
GPIIB/IIIA
Platelet cohesion binds to
circulating fibrinogen and
cross-links adjacent
platelets to promote
aggregation.
(1) Agonists of platelet aggregation induce Fibrinogen Mechanism
conformational changes in GP IIb/ IIIa
receptors that permit fibrinogen binding
of Binding
TXA2
ADP
Serotonin (2) Fibrinogen simultaneously binds to GP IIb/ IIIa
receptors on 2 separate and activated platelets-
promotes aggregation

++
AGONIST AGONIST
AGONIST
RECEPTORS RECEPTORS
RECEPTORS

RESTING ++ ACTIVATED ACTIVATED

PLATELET PLATELET PLATELET

Inactive GP IIb/ IIIa Active GP IIb/ IIIa Fibrinogen

Receptor Receptor
GP IIb/ IIIa Receptor Antagonist Mechanism

Fibrinogen

AGONIST AGONIST
AGONIST
RECEPTOR RECEPTOR
RECEPTOR

RESTING (++) ACTIVATED ABCIXIMAB ACTIVATED

PLATELET PLATELET EPTIFIBATIDE PLATELET
TIROFIBAN

Inactive GP IIb/ IIIa Active GP IIb/ IIIa Fibrinogen

Receptor Receptor
Indications and Adverse GPIIB/IIIA Antagonists
Indications
*Prevention of thrombosis during and after coronary
artery procedures such as angioplasty
*Not drug of choice for emergency surgery because
bleeding can take a half day to normalize

Pharmacokinetics
*Short plasma half-life (10-30 min)
*Long duration of action (>2 days) long action is
due to slow dissociation rate from
GPIIB/IIIA receptors

Adverse Effects
(no antidote)
*Bleeding
 Anticoagulant Drugs

Decrease synthesis or Decrease synthesis of vitamin K

or activity of thrombin which leads to inactive clotting factors
 Classes of Anticoagulant Drugs
Drug Site of Action Cellular Effect Administration Representative
Route Drugs
Heparin Anti-thrombin III thrombin activity Parenteral Heparin
thrombin synthesis

Low Molecular Anti-thrombin III thrombin synthesis Parenteral Enoxaparin

Weight Dalteparin
Heparin Tinzeparin
(LMWH)
Direct Factor Thrombokinase thrombin synthesis Oral Xabans
Xa Inhibitors (also called Rivaroxaban
(xabans) Factor Xa or Apixaban
prothrombinase)

Direct Thrombin thrombin activity Oral Dabigatran

Thrombin Parenteral Argatroban
Inhibitors Parenteral Bivalirudin

Warfarin Vitamin K- vitamin K synthesis Oral Warfarin

dependent synthesis of active
reductase clotting factors
 Heparin Mechanism of Action
Prothrombin
Thrombokinase Synthesis
(Prothrombinase) + _ 2
(Factor Xa) 1
Thrombin _ Anti-thrombin III + Heparin
Activity

Fibrinogen + Fibrin
(soluble) (insoluble)
1 Anti-thrombin III is an -globulin that binds to thrombin and decreases its affinity for
fibrinogen. The result is reduced activity of thrombin which slows the rate at
which fibrinogen is converted into fibrin on the activated platelets. This slows the rate
of coagulation and reduces the probability of thrombus formation. It also interacts with
thrombokinase to reduce synthesis of new thrombin molecules.
BUT under normal physiological conditions, anti-thrombin-III interacts very slowly
with thrombin or thrombokinase. This means that the rate of thrombin inactivation
by anti-thrombin III is physiologically slow.
2 Heparin binds directly to anti-thrombin-III. This induces a conformational change in
anti-thrombin-III which increases its affinity for thrombin and thrombokinase. The net
effect is that anti-thrombin-III binds more rapidly to thrombin and thrombokinase
resulting in a greater decrease in thrombin synthesis and activity and a more rapid, and
greater, reduction in fibrin levels. Therefore, heparin slows coagulation by accelerating
or enhancing the ability of anti-thrombin to block thrombin-induced coagulation.
 Heparin versus LMWHs:
Size Difference Effects
Mechanism of Action

HEPARIN
(Unfractionated)

ENOXAPARIN
(LMWH)
 Thrombokinase _
(Factor Xa)
Drug-nave
Prothrombin
+ Thrombin _ Anti-thrombin III patient

+
Fibrinogen Fibrin HEPARIN complexes with anti-thrombin
III: this increases anti-thrombin III affinity
for existing thrombin molecules and for
thrombokinase which leads to enhanced
Thrombokinase inhibition of both thrombin activity and
_ synthesis of new thrombin molecules; end
(Factor Xa)
result is less active thrombin molecules and
decreased fibrin production. The large size
+ (and extensive negative charge) of heparin
Prothrombin Thrombin _ Anti-thrombin III also allows it to interact directly with
thrombin molecules (i.e., heparin interacts
Heparin directly with anti-thrombin III and
thrombin). The interaction with both anti-
+ thrombin II and thrombin is the major
Fibrinogen Fibrin mechanistic distinction from LMWHs and is
because of heparins size.

Thrombokinase LMWHs also complex with anti-thrombin

III but the result is much greater inhibition
(Factor Xa) _
of thrombokinase activity rather than the
activity of existing thrombin molecules.
LMWHs do not interact directly with
+ Thrombin existing thrombin because they are smaller
Prothrombin _ Anti-thrombin III
than the parent compound heparin and lack
LMWH enough negative charge. Relative to heparin,
LMWHs produce a more selective effect
+ through preventing the synthesis of new
Fibrinogen Fibrin thrombin.
 Heparin Pharmacology
Heparin
Hydrophilic does
not penetrate brain
or placental barrier
and not well absorbed
from GI tract.

Major Therapeutic Uses

Pulmonary embolism
Myocardial infarction
Major anticoagulant drug for pregnant women
(does not cross placenta or blood-brain barrier)

Major Side Effects

Excessive Bleeding (antidote is protamine sulfate)
Hypersensitivity/allergic reactions
Mineralocorticoid deficiency
Hair Loss
Direct Thrombokinase (Factor Xa)
and Direct Thrombin Inhibitors

Major mechanistic distinction versus heparin and LMWHs:

Do not require interactions with the cofactor
anti-thrombin III for their anticoagulant efficacy.
 Direct Factor Xa Inhibitors
(Thrombokinase Inhibitors)
Thrombokinase _ Rivaroxaban
Apixaban (FDA 2012)
Oral and infrequent dosing
Predictable effects/ limited drug interactions

+
Prothrombin Thrombin

+
Fibrinogen
Fibrin
 Direct Thrombin Inhibitors (DTIs)
(Bivalent Inhibitors)
Thrombokinase
Dabigatran (Pradaxa)
Argatroban

_
Dabigatran (oral)
+ Competitive, reversible thrombin inhibition
Prothrombin Thrombin Versus warfarin: similar efficacy but does not
require blood test monitoring (warfarin does)
Major Adverse Effect: GI bleeding (due to
tartaric acid present in capsules low pH is
+ required for absorption)
Fibrinogen Idarucizumab is antidote for adverse effects
Fibrin
(reverses effects of dabigatran within min)

Argatroban (parenteral, [IV])

Major Therapeutic Use: Treatment of HIT
(heparin-induced thrombocytopenia )
No antidote therapy to reverse adverse effects
Does require blood monitoring
 Direct Thrombin Inhibitors (DTIs)
(Univalent Inhibitors)
Thrombokinase Hirudin
Bivalirudin

_
Bivalirudin (parenteral [IV])
+ Competitive, reversible thrombin inhibition
Prothrombin Thrombin Rapid onset and short duration of action
Versus heparin:
*much more selective action only binds to
circulating and clot-bound thrombin; does not
+
Fibrinogen bind to other proteins or red blood cells
Fibrin *does not produce HIT (heparin-induced
thrombocytopenia
 Mechanistic Difference for DTIs:
Univalent versus Bivalent Thrombin Inhibition

HEPARIN
BINDING SITE BIVALENT
(FIBRINOGEN) INHIBITOR
(exosite 2)
Hirudin
CATALYTIC
Bivalirudin
SITE
Inhibits catalytic site and
substrate (fibrinogen) site (exosite 1)

SUBSTRATE UNIVALENT
RECOGNITION SITE INHIBITOR
(FIBRINOGEN)
(exosite 1)
Dabigatran (Pradaxa)
Argatroban
Inhibits only substrate (fibrinogen) site (exosite 1)
Vitamin K Antagonists

4-hydroxycoumarin

Warfarin Dicumarol
Carboxylated Clotting Factors (e.g. Prothrombin) are
Required for Coagulation
Clotting Factor
O Carboxylation

CO2 O2 C O-
Prothrombin Prothrombin Thrombin
(inactive) Vitamin K (reduced) (active)

Coagulation
WARFARIN
DICUMAROL
Vitamin K-dependent, post-translational carboxylation of clotting factors (including
prothrombin) is necessary for interaction between the clotting factors and platelet
membranes. The production of carboxylated clotting factors depends on adequate
supply of REDUCED vitamin K. Any drug that decreases the regeneration of reduced
vitamin K will result in the production of decarboxylated clotting factors (e.g.
prothrombin) which will slow the coagulation rate.
Vitamin K Antagonist Mechanism Components

Prothrombin (several Protein Factors)

Reduced Vitamin K-H2
Oxidized Vitamin K-O (Vitamin K epoxide)
Vitamin K-dependent Carboxylase
Vitamin K Epoxide Reductase
NADPH
Warfarin/ Dicumarol
 Vitamin K Antagonist Mechanism
CH2__CH2__COOH
Prothrombin
(decarboxylated) Vitamin K-H2
O2 + CO2 NADP+
(Reduced)

Vitamin K-dependent
carboxylase Vitamin K Epoxide
Reductase

Vitamin K-O
(Oxidized) NADPH
COO-
CH2__CH__COO-
Prothrombin
(carboxylated)
 Vitamin K Antagonist Mechanism
CH2__CH2__COOH
Prothrombin
(decarboxylated) Vitamin K-H2 NADP+
CO2
(Reduced)

Vitamin K-dependent
carboxylase Vitamin K Epoxide
Reductase

Vitamin K-O
(Oxidized) NADPH
COO-
CH2__CH__COO-
Prothrombin
(carboxylated)
WARFARIN
 Vitamin K Antagonist Mechanism Summary
Mechanism
Normal Vitamin K Role
Several protein factors require Vitamin K for post-translational modification (e.g. Factor
II- prothrombin) during their synthesis in liver
Glutamic acid residues are carboxylated- the reaction requires reduced Vitamin K
(Vitamin K-H2) as coenzyme; a carboxylase enzyme (Vitamin K-dependent
carboxylase) catalyzes the reaction
Decarboxylated prothrombin is inactive (no clotting occurs)
Carboxylated prothrombin is active (carboxylated side chains interact with calcium
ions and membrane lipids to complete the clotting process)
Reduced Vitamin K (Vitamin K-H2) is oxidized during the carboxylation reaction to
oxidized Vitamin K-O (called Vitamin K epoxide)
Reduced Vitamin K (Vitamin K-H2) must be regenerated for carboxylation reaction to
continue and for active (carboxylated) prothrombin to form
Enzyme (Vitamin K Epoxide Reductase) converts (reduces) oxidized Vitamin K-
O to reduced Vitamin K-H2 reaction requires NADPH

Vitamin K Antagonist Role

Warfarin inhibits Vitamin K Epoxide Reductase
Prevents regeneration of reduced Vitamin K (Vitamin K-H 2)
Without reduced Vitamin K, prothrombin side chains are not carboxylated
Thus, inactive (decarboxylated) prothrombin and other inactive protein factors are
formed
Overall, coagulation is inhibited
 Vitamin K Antagonists (Pharmacokinetics, Side Effects)

Therapeutic Uses
Anticoagulant (effects can be overcome by administration of vitamin K).

Pharmacokinetics (be able to contrast with heparin/enoxaparin)

Slow onset of action
100% bioavailability
99% albumin bound
Catabolized by cytochrome P450 enzymes
Crosses both placental and blood-brain barriers

Side Effects and Contraindications

Bleeding (hemorrhaging)
Contraindications
Pregnancy (fetal hemorrhaging by preventing carboxylation of fetal proteins).
Vitamin K deficient patients
 Warfarin (Drug Interactions)
WARFARIN EFFICACY
(1) Broad Spectrum Antibiotics (amoxicillin, ampicillin): they inhibit
intestinal bacteria that synthesize vitamin K and decrease the quantity of
vitamin K which drives clotting factor carboxylation.
(2) Alcohol: compete with warfarin for metabolism by cytochrome P450
enzymes. This increases the amount to time that warfarin remains in
plasma.

WARFARIN
(1) Vitamin K administration: the increase in reduced vitamin K
circumvents the warfarin block of vitamin K epoxide reductase- the
increase in vitamin K. Allows for the formation of active, carboxylated
clotting factors.
(2) Barbiturates: induction of cytochrome P450 enzymes- this increases the
numbers of these enzymes, leading to more efficient warfarin metabolism
(3) Cholestyramine: inhibition of warfarin absorption from GI tract
(4) Chronic Alcohol exposure: ?

WARFARIN EFFICACY
 Heparin Versus Warfarin
Variable Heparin Warfarin
Site of Action Anti-thrombin III Vitamin K epoxide
reductase
Mechanism of Reduction in activity and Reduction in Vitamin K
Action synthesis of thrombin production leading to
inactive clotting factors
Administration Parenteral (Intravenous) Oral
Onset of Action Immediate (Intravenous) Slow (24 h)

Duration of Relatively short (2-4 h) Relatively Long (days)

Action
Adverse Effects Bleeding, hypersensitivity, Bleeding
allergy, aldosterone deficiency
Antidote for Protamine Sulfate Vitamin K infusion
Bleeding
Chemistry Hydrophilic (poor penetration Lipophilic (penetration of
of cells and barriers) cells and barriers)
 Thrombolytic Drugs (General)
Commonalities (see general mechanism below)
Enhance fibrolysis (degradation of the soluble fibrin strand) by
either directly or indirectly activating the conversion of
plasminogen into plasmin. In turn, the increased levels of
plasmin then accelerate the degradation of fibrin.
More effective when administered soon after clot formation.
Usually administered IV to ensure rapid onset of action.

Fibrin
(insoluble)
_ Plasmin attacks and erodes
fibrin strands- this breaks
Plasminogen Plasmin down fibrin meshwork and
+ erodes blood clot
tPA catalyzes conversion of
plasminogen into active enzyme plasmin

Other Thrombolytic Tissue Plasminogen

Agents Activator (tPA)
 Individual Thrombolytic Drugs
Thrombolytic Mechanism of Action
Alteplase *Directly converts plasminogen
(tPA) into plasmin - is said to be
'fibrin-selective' because it
has high affinity for
plasminogen bound to fibrin
but only low affinity for
unbound plasminogen.
*similar mechanism to alteplase
Reteplase
Streptokinase No enzymatic activity by itself:
instead, it forms a 1:1
complex with plasminogen
(i.e., streptokinase-
plasminogen complex) which
then converts plasminogen
into plasmin.
Anistreplase Mechanism similar to alteplase
and is 'fibrin-selective'.
Other
*Good adverse effect profile because
it does not attack unbound
plasminogen.
*Excellent at dissolving old clots.
*Very short half-life of about 5 min.
*Versus alteplase: smaller, more
potent, faster, longer duration
*Not 'fibrin-selective' - it targets
plasmin that is both in circulation
and attached to fibrin.
*Short half-life of about 30 min.
*Relatively longer half-life (90 min).