Anticoagulant, Fibrinolytic and

Antiplatelet Drugs

Introduction to Pharmacology I

Kishore Pasumarthi
([email protected])
Oct 29, 2008

NB: This handout does not have ALL the

information......
 Overview
• Describe basic physiology of blood coagulation
- Anticoagulant drugs

• Describe basic physiology of fibrinolysis

- Fibrinolytic drugs

• Describe role of platelets in blood coagulation

- Antiplatelet drugs

• Management of clotting disorders

 Background
• Hemostasis is a highly regulated process:
- maintains the fluidity of the blood,
- limits
li it lloss off bl
blood
d ffrom a d
damagedd bl
blood
d vessel,
l
- prevents vessel occlusion (thrombosis)

• Failure of hemostasis mechanisms can lead to:

- excessive bleeding (or)
- vessel occlusion by excessive blood clot formation
(thrombosis)

• Drugs used to prevent thrombosis are classified as

anticoagulant, fibrinolytic and antiplatelet drugs.
 Clinical significance of thrombosis
• Damage to vessel wall can initiate the formation of a
blood clot (thrombus).
- excessive thrombosis is seen in:

• A blood
bl d clot
l t can occlude
l d bl
blood
d flflow causing
i iischemia
h i iin
various organs such as heart, brain and kidney.
- this can lead to:

• Abblood
ood cclot
o formed
o ed in oone
e ssite
e ca
can b
break
ea ooff a
and
d travel
a e
to remote sites and occlude smaller blood vessels. This
process is called thromboembolism.
 Blood Clotting
• Highly regulated process involving platelets as
well as various cellular and blood clotting factors.

• Two physiological steps involved:

1) Thrombogenesis

2) Blood coagulation
 Thrombogenesis
• Platelet adhesion and aggregation:

• Platelet plug:

• Fibrin
Fib i RReinforcement:
i f t
 Vessel wall Collagen Endothelium
damage

ADP
Platelet 1) Platelet adhesion
TXA2
5-HT and aggregation
Platelet 2) Formation of weak
+ platelet
l t l t plug
l
Platelet
3) Fibrin
Extrinsic Intrinsic Reinforcement
Xa
+
+ Fibrin
+ Blood
Prothrombin Thrombin
Coagulation
Fibrinogen
 Blood Clot

Yuri Veklich and John W. Weisel, University of Pennsylvania School of Medicine

 Blood Coagulation

• Transformation of soluble fibrinogen into insoluble fibrin.

• Many blood clotting factors interact in a cascading series

of limited proteolytic reactions.

• Extrinsic and intrinsic pathways: converge at factor X to

produce thrombin which catalyses the transformation of
soluble fibrinogen to insoluble fibrin.

• Extrinsic pathway (The main initiator of blood coagulation)

– Is activated by tissue factor (TF)/factor VIIa pathway

• Intrinsic pathway
– activated
acti ated by
b surface
s rface contact with
ith a foreign body
bod
 Schematic of Blood Coagulation
Tissue injury
Abnormal
vessel wall
Extrinsic
XIIa XII

Intrinsic
VII + TF VIIa XIa XI

Ix IXa IX

X Xa

II IIa
Prothrombin Thrombin

I Ia
Fibrinogen Fibrin Clot
NOT ON EXAM
 Anticoagulant Drugs
• Heparin (Enoxaparin) (LMWH):
• Binds to and stabilizes antithrombin which inhibits many
clotting factor proteases (1000x enhanced activity)
• 1st line therapy (acts quickly)
• Administration
Administration: by
b II.V.
V or S
S.C.
C injection
• Indications: embolisms, prophylactic (low dose
SC)
S.C.),
• Toxicity: excessive bleeding therefore closely
monitor especially in elderly and renal failure
monitor,
patients, thrombocytopenia occurs in 25% or
more of patients
p
• Antidote: protamine sulfate a specific antagonist
 Extrinsic
E i i Intrinsic
clotting cascade clotting cascade

Xa
Heparin
Prothrombin Thrombin
Antithrombin
Fibrinogen Fibrin Clot 1000X
 Anticoagulant Drugs
• Hirudin
– Specific irreversible thrombin inhibitor isolated from
the leech available as recombinant form (lepirudin)

– Administration: same as Heparin

– Indications: for patients who have developed

thrombosis secondary to heparin-induced
heparin induced
thrombocytopenia

– Toxicity: up to 40% of patients on long

long-term
term
infusions can develop allergy (forming antibodies
to thrombin-lepirudin complex), no antidote
 Extrinsic
E i i Intrinsic
clotting cascade clotting cascade

Xa

Prothrombin Hirudin
Thrombin

Fibrinogen Fibrin Clot

 Anticoagulant Drugs
• Warfarin member of coumarin family
– blocks γ−carboxylation of glutamate residues in
prothrombin and factors ((VII,, IX,, X)) leaving
p g them
biologically inactive

– Administration: Taken orally,

orally 8
8-12
12 hours until onset of
action, long half life (~36 hours)

– Indications: Treatment of thromboembolisms,

Prophylactic (often given after MI), rodent infestations

– Toxicity: Can cross placental barrier, several drug

interactions leading to increased bleeding.

– Antidote: vitamin K
 Mechanism of Warfarin Action

Descarboxy-
b CO2
prothrombin carboxylase Prothrombin
Coupled
Active
A i Inactive
Vitamin K O2 vitamin K
(catalyst)
y

Epoxide
p
Antidote: hydrolase
Vitamin K
Supplementation
Warfarin
 Regulation of Coagulation

• Fibrin Inhibition: Plasma protease inhibitors (such

as alpha2 macroglobulin
macroglobulin, antithrombin) block
fibrin formation.

• Fibrinolytic Enzymes: Thrombus is digested by

proteolytic enzymes (tissue plasminogen
activator
ti t (t-PA),
(t PA) urokinase
ki etc.)
t )
 Fibrinolysis

Plasminogen

Aminocaproic acid
t-PA, urokinase +

Plasmin

Thrombin Fibrin split

Degradation Fibrinogen Fibrin
products products
d
 Fibrinolytic Drugs (Clot-Busters)
• Streptokinase
– is a bacterial protein that combines with
plasminogen
l i tto catalyze
t l th
the conversion
i off
plasminogen to plasmin (not selective for fibrin-
bound plasminogen)

• Urokinase
– Human
H enzyme converts
t plasminogen
l i tto plasmin
l i
• very expensive, thousands of dollars

• Alteplase
– recombinant human t-PA (tissue plasminogen
activators)
 Fibrinolytic Drugs (cont)
• MOA:
– Lyse thrombi by catalyzing the formation of plasmin
– t-PA
t PA preferentially activates plasminogen bound to
fibrin confining fibrinolysis to formed thrombus avoids
systemic activation
• Administration: I.V. (5
( min-12 hrs))
• Indications:
– multiple
lti l pulmonary
l emboli,
b li central
t ld deep vein
i
thrombosis
– acute myocardial infarction (can reduce mortality by
20% in MI patients)
– patients presenting with acute stroke symptoms given
within 3 hours of onset
• Toxicity: allergies and bleeding
 Platelet Function
• Platelet function can be regulated 3 ways:
1) autocrine
t i stimulation
ti l ti - made d bby platelets
l t l t tto
interact with their own receptors (ADP, PG, 5-
HT etc.)
etc )
2) agents made by platelets which function
cAMP Ca2+ etc.)
internally (TXA2, cAMP, etc )
3) external agents that interact with their
membrane receptors (Collagen, thrombin,
prostacyclin)

*Antagonists exist for all 3 levels of platelet activation*

 Vessel wall Collagen Endothelium
damage

ADP
Platelet 1) Platelet adhesion
TXA2
5-HT and aggregation
Platelet 2) Formation of weak
+ platelet
l t l t plug
l
Platelet
3) Fibrin
Extrinsic Intrinsic Reinforcement
Xa
+
+ Fibrin
+ Blood
Prothrombin Thrombin
Coagulation
Fibrinogen
 Antiplatelet Drugs
• Aspirin (acetylsalicylic acid)

• MOA: irreversibly acetylates cyclooxygenase-

1 blocking the synthesis of thromboxane A2
1,
(TXA2), therefore blocking its platelet-
aggregating action

• Indications: Prophylaxis
p y of MI ((350mg/d)
g )

• Toxicity: stomach ulcers, bleeding

 Antiplatelet
p Drugs
g
• Thienopyridines (Clopidogrel)
• MOA: inhibit ADP pathway by irreversibly
inhibiting binding to its receptor (reducing its
platelet
l t l t aggregating
ti effects)
ff t )
• Administration: Oral dose (300mg then
75mg/d)
• Indications: prohylaxis in stroke, MI patients
• Toxicity:
T i it stomach
t h irritation,
i it ti di
diarrhea,
h
hemorrage, leukopenia (rare)
 Antiplatelet Drugs
• Glycoprotein IIb/IIIa inhibitors:
• Abciximab (Ab),
– MOA: bind GPIIb/IIIa receptors inhibits the
final common pathway in platelet
aggregation
– Administration: I.V.

Platelet
GP
IIb/IIIa
Fibrinogen

Platelet
 Vessel wall Collagen Endothelium
damage

ADP vWF
TXA2 Platelet
5-HT
Antiplatelet drugs
(Aspirin,
Thienopyridines,
GPIIb/III bl
GPIIb/IIIa blockers)
k )
+
Platelet
 Arterial Thrombosis

• Patients with transient ischemic attacks,

attacks
strokes, unstable angina, or myocardial
infarction
– Treatment with aspirin, clopidogrel
– In angina and infarction often combined with a
fibrinolytic drug such as urokinase, or
alteplase
 Summary
– Prophylactic
P h l ti ttreatment
t t mainly
i l with
ith
• Anticoagulants
– LWMH,, Warfarin
• Antiplatelets
– Aspirin, Clopidogrel

– Acute treatment with one or in combination

• Anticoagulant,
g , Antiplatelet,
p , and /or Fibrinolytic
y
Drugs