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Drugs that affect hemostasis
Ahmad Shihada Silmi Msc, FIBMS
IUG
Faculty of Sciences
Medical Technology Dep.
Drugs that affect hemostasis
Drugs are categorized according to
the process they target.
An injured blood vessel
 Contracts
 Forms a platelet plug (1º hemostasis)
 Forms a protein clot (2º hemostasis)
 Once healed, solubilizes the clot
(fibrinolysis)
Drugs Affecting Hemostasis
Anticoagulants
Therapeutic overview
Heparin and heparin derivatives
Coumarins (warfarin)
Directly acting thrombin inhibitors
hirudin
bivalirudin
argatroban
arterial thrombosis
atrial fibrillation
cardiomyopathy
cerebral emboli
heart valve disease
hip surgery
vascular prostheses
Venous
thromboembolism
Oral
anticoagulants
4-Hydrdroxycoumarin
and indan-1,3-dione
are the parent
molecules.
Warfarin
Interferes with the synthesis of the
vitamin K-dependent clotting factors
MechanismDrugs Affecting Hemostasis
Mechanism of Action
Interferes with liver synthesis
Vitamin K
VII
Synthesis
IX
of
X Functional
Coagulatio
II n Factors
C Synthesis
of AntiS
coagulatio
Z n Proteins
Drugs Affecting Hemostasis
Vitamin K Action
Drugs Affecting Hemostasis
Warfarin Mechanism of Action
Drugs Affecting Hemostasis
Warfarin Pharmacokinetics
ABSORPTION: Rapid, complete. Used
orally.
 DISTRIBUTION: Vd is small; plasma
protein binding ≈ 99%.
 [Maternal] = [Fetal]. Warfarin is not found
in breast milk; other coumadins are!
 ELIMINATION: T1/2 = 40 hr.


ONSET:
2-3 days.

DURATION: 2-5 days.
Drugs Affecting Hemostasis
Warfarin: Adverse Actions



Bleeding is the main concern
 vitamin K, clotting factors, fresh
frozen plasma
Crosses the placenta and is
teratogenic during weeks 6-12
Alopecia, urticaria, dermatitis,
fever, nausea, diarrhea, abdominal
cramps, anorexia, skin necrosis
Drugs Affecting Hemostasis
Drug Interactions
Drug interactions are particularly important with oral anticoagulants, and the result may be
either an increase or a decrease in the effect of the anticoagulant. Frequent monitoring of
the prothrombin time is essential when administering another drug with warfarin, and
changing the dose of warfarin may be necessary.
Drugs increase anticoagulation by
1.
Displacement of protein bound warfarin. Because of the high degree of warfarin bound to
plasma proteins, even a small decrease in the amount bound can lead to significant increases
in free drug levels. Examples: salicylates such as aspirin.
2.
Inhibition of the liver microsomal enzyme system that metabolizes warfarin will increase the
availability of warfarin. Example: quinidine.
3.
Increasing the warfarin “receptor site” affinity will increase the efficacy of a given plasma
level of warfarin. Example: d-thyroxine.
4.
Reducing the availability of vitamin K. Example: broad spectrum antibiotics, laxatives.
5.
Inhibiting platelet function. Example, aspirin.
Drugs depress anticoagulation by
1.
Stimulation of the hepatic microsomal enzyme system. This decreases plasma half-life of
warfarin. Example: barbiturates.
2.
Stimulation of clotting factor synthesis. This antagonizes the effect of warfarin. Example:
vitamin K, estrogens.
3.
Inhibition of absorption. Example: cholestyramine.
Drugs Affecting Hemostasis
Heparin

2-40 kDa MW, naturally occurring N- & Osulfated sugars polymerized by glycoside
bonds found in the secretory granules of
mast cells.
Drugs Affecting Hemostasis
Heparin


2-40 kDa MW, naturally occurring N- & O-sulfated
sugars polymerized by glycoside bonds found in
the secretory granules of mast cells.
Lower MW polymers possess most of the
biological activity.

Active in vitro as well as in vivo.

The most acidic organic acid in the body.

Is not absorbed following oral administration.
Drugs Affecting Hemostasis
Mechanism of Action

Accelerates the inactivation of factors IIa,
Xa, IXa, XIa and XIIa by the serine protease
inhibitor, antithrombin III (AT III).
Drugs Affecting Hemostasis
Mechanism of Action

Unique pentasaccharide sequence binds to
antithrombin III (AT III) with high affinity but
a polysaccharide of at least 18 units is
required (5 for LMWH).
Drugs Affecting Hemostasis
AT III
+
Heparin
Serine
protease
Inactive
Drugs Affecting Hemostasis
Ternary complex
LMW Heparin






MW 4,000 - 6,000
Preferentially binds to factor Xa
T1/2 2x > standard heparin
Less bleeding
Less effect on platelet activation
and factor XIII activation
Clinically effective - e.g.,
enoxaparin
Drugs Affecting Hemostasis
AT III
IIa
Heparin
Heparin
> 18 monosaccharide
units
AT III
< 18 monosaccharide
units
Heparin
AT III
LMWH
Drugs Affecting Hemostasis
Xa
Heparin Pharmacokinetics



No oral absorption; IV or subQ.
Vd is small due to extensive
binding. Binding can influence the
effect of heparin.
Onset: IV, immediate; subQ, 20-60
min
Drugs Affecting Hemostasis
Heparin Adverse Actions
Bleeding is the main concern.




Antidote: protamine sulfate.
Thrombocytopenia (<5%, within a few days).
Disappears with cessation of therapy.
Rapid and profound thrombocytopenia (<5%, 8-10
days) with paradoxical arterial or venous thrombosis.
Results from the formation of anti-heparin antibodies.
Heparin-Ab bind to platelets causing inappropriate
aggregation and thrombus formation. May be lifethreatening.
Reversible osteoporosis (6 months). If it occurs, it is
usually after 6 months therapy with >15,000 U/day.
Drugs Affecting Hemostasis
Antiplatelet Drugs
Drugs Affecting Hemostasis
Therapeutic overview
Platelet aggregation inhibitors
Aspirin
Cerebrovascular accident, stroke,
coronary bypass surgery,
coronary angioplasty/stenting or
thrombolysis, myocardial
infarction, transient ischemic
attack
Clopidogrel
Coronary artery disease,
cerebrovascular accident, stroke,
peripheral arterial disease
Glycoprotein
IIb/IIIa inhibitors
Acute coronary syndromes, after
coronary artery stenting
Aspirin Mechanism of Action
Aspirin irreversibly inactivates
cyclooxygenase by covalent
acetylation.
Drugs Affecting Hemostasis
Aspirin
inhibits
Aspirin
inhibits
Selectivity of aspirin for platelet COX
1. Platelet COX is acetylated in the
portal circulation before aspirin is
deacylated in the liver.
2. The systemic vasculature is
unaffected because platelets are not
affected by salicylate.
Drugs Affecting Hemostasis
Aspirin Pharmacokinetics





ABSORPTION: 70%
DISTRIBUTION: at low doses most is
protein bound in plasma; at high doses a
smaller percentage is bound and more is
available to tissues
ELIMINATION: hepatic metabolites
(75%) and parent compound excreted in
urine. At low doses half-life is 4 hr and
is 1st order. High doses show saturation
kinetics and half-life is 15 hr. Faster in
alkaline urine.
ONSET: 30 min
DURATION: 7-10 days
Drugs Affecting Hemostasis
Aspirin Adverse Actions
Primarily gastrointestinal

Epigastric pain, heartburn, nausea

GI blood loss

Gastric ulcer

Others: rash, tinnitus, nasal polyps,
gout, acid-base disturbances
Drugs Affecting Hemostasis
Aspirin Drug Interactions



Decreases the effectiveness of
antihypertensives: usually not a
problem with low doses.
Increases the effect of warfarin.
Attenuates the actions of uricosuric
agents, e.g. probenecid.
Drugs Affecting Hemostasis
Ticlopidine and Clopidogrel
P2Y2 purine receptor antagonists.
Drugs Affecting Hemostasis
Other Antiplatelet Drugs
Ticlopidine and Clopidogrel: P2Y2 purine receptor
antagonists
clopidogrel

P2Y2R
A
C
J. L. et Hemostasis
al. J. Biol. Chem. 1998;273:2024-2029
DrugsDaniel,
Affecting
P2Y1
R
Clopidogrel



Reduces the incidence of stroke and
myocardial ischemia.
Particularly effective combined with
aspirin.
Currently the drug of choice in the
prophylaxis of subacute stent thrombosis
and post ischemic stroke treatment.
Drugs Affecting Hemostasis
Glycoprotein IIb/IIIa Inhibitors
GP IIb/IIIa is a platelet surface integrin
(aIIb3)


GP IIb/IIIa is the receptor for fibrinogen
and von Willebrand factor.
Thrombin, collagen, TXA2 activate
platelets exposing binding sites for vWf
and fibrinogen.
Drugs Affecting Hemostasis
Basal platelet
with GP
IIb/IIIa
receptors in
inactive state
Activated platelet
with functional
GP IIb/IIIa
receptors
Agonis
t
Fibrinog
en
GP
IIb/IIIa
antagonis
t ()
Fibrinogen binding
to platelets blocked
by GP IIb/IIIa
receptor antagonist
Fibrinogen
mediated
platelet
aggregation
Glycoprotein IIb/IIIa Inhibitors
 Abciximab -- Fab fragment directed to
the GPIIb/IIIa receptor. Can be used
only once.
 Eptifibatide -- a cyclic peptide
 Tirofiban -- a nonpeptide inhibitor
Drugs Affecting Hemostasis
Fibrinolytics
Restore blood flow to an injured
area by lysing the thrombus into
soluble fibrin degradation products.
Drugs Affecting Hemostasis
Alteplase (rtPA)
Urokinase
Streptokinase
Anistreplase
Drugs Affecting Hemostasis
Site of action of drugs acting on the fibrinolytic system. Fibrinolytic drugs accelerate the conversion of plasminogen to
plasmin, which is a protease that breaks down fibrinogen and fibrin to degradation products.
© 2005 Elsevier
tPA
Plasminogen
Plasminogen
L
L
Plasmin
tPA
L
Fibrin Clot
tPA
Plasmin
L
L
L
tPA, tissue plasminogen
activator
Fibrin Clot
L, lysine binding sites
PI
PI, plasmin inactivator
Plasmin
Drugs Affecting HemostasisSoluble fibrin
digestion products
Treatment Goals
Rapid reperfusion of the infarcted area
to preserve more tissue.
Drugs Affecting Hemostasis
Fibrinolytic success is dependent
upon the time lapse between the
onset of symptoms and
administration of the fibrinolytic.
• DVT: <
7 days
• Pulmonary embolism: <
• Myocardial infarction:
• Stroke: < 3 hr
Drugs Affecting Hemostasis
2 days
2 - 4 hr
Fibrinolytics: Adverse Actions
Unwanted BLEEDING is the MAJOR
side effect.
Drugs Affecting Hemostasis
The
End
Drugs Affecting Hemostasis