ANTI

COAGULANT
& ANTI
PLATELETS
Presented by: Laraib Faisal

Presented to: Dr. Irfan Hamid

HEMOSTASIS
›Thrombosis, the formation of an unwanted clot within a blood vessel,
is the most common abnormality of hemostasis.
›Thrombotic disorders include
Øacute myocardial infarction (MI),
Ødeep vein thrombosis (DVT),
Øpulmonary embolism (PE),
Øacute ischemic stroke.
›These conditions are treated with drugs such as anticoagulants and
fibrinolytics.
›Bleeding disorders involving the failure of hemostasis are less
common than thromboembolic diseases.
These disorders include hemophilia, which is treated with
transfusion of recombinant factor VIII, and vitamin K deficiency,
which is treated with vitamin K supplementation
Thrombus verses emboli
• A clot that adheres to a vessel wall is called a “thrombus,” whereas
an intravascular clot that floats in the blood is termed an “embolus.”
• detached thrombus becomes an embolus.
• Both thrombi and emboli are dangerous, because they may occlude
blood vessels and deprive tissues of oxygen and nutrients.
• Arterial thrombosis most often occurs in medium-sized vessels
rendered thrombogenic by atherosclerosis.
• Arterial thrombosis usually consists of a platelet-rich clot.
• In contrast, venous thrombosis is triggered by blood stasis or
inappropriate activation of the coagulation cascade.
• Venous thrombosis typically involves a clot that is rich in fibrin,
with fewer platelets than are observed with arterial clots.
Classification of Drugs:
Platelet response to vascular
injury
• Physical trauma to the vascular system, such as a puncture or a cut,
initiates a complex series of interactions between platelets, endothelial
cells, and the coagulation cascade.
• These interactions lead to hemostasis or the cessation of blood loss from a
damaged blood vessel.
• Platelets are central in this process.
• 1:Initially, there is vasospasm of the damaged blood vessel to prevent
further blood loss.
• 2:The next step involves the formation of a platelet–fibrin plug at the site
of the puncture.
• The creation of an unwanted thrombus involves many of the same steps
as normal clot formation, except that the triggering stimulus is a
pathologic condition in the vascular system, rather than external physical
trauma(eg, myocardial infarction, ischemic stroke)
1:Resting
platelets
 Platelets act as vascular
sentries, monitoring the
integrity of the vascular
endothelium.
 In the absence of injury,
resting platelets circulate
freely, because the
balance of chemical
signals indicates that
the vascular system is
not damaged
2: Release of Prostacylin and
NO2
• Chemical mediators, such as prostacyclin and
nitricoxide, are synthesized by intact endothelial
cells and act as inhibitors of platelet aggregation.
• Prostacyclin (prostaglandin I2 ) acts by binding to
platelet membrane receptors that are coupled to
the synthesis of cyclic adenosine monophosphate
(cAMP), an intracellular messenger .
• Elevated levels of intracellular cAMP are associated
with a decrease in intracellular calcium.
• This prevents platelet activation and the
subsequent release of platelet aggregation
agents.
• Damaged endothelial cells synthesize less
prostacyclin than healthy cells, resulting in lower
prostacyclin levels.
• Since there is less prostacyclin to bind platelet
receptors, less intracellular cAMP is synthesized,
which leads to platelet aggregation.
Roles of thrombin, thromboxanes, and
collagen:
• The platelet membrane also contains receptors that can bind
thrombin, thromboxanes, and exposed collagen.
• In the intact, normal vessel, circulating levels of thrombin
and thromboxane are low, and the intact endothelium covers
the collagen in the subendothelial layers.
• The corresponding platelet receptors are, thus, unoccupied,
and as a result, platelet activation and aggregation are not
initiated.
• However, when occupied, each of these receptor types triggers
a series of reactions leading to the release into the circulation
of intracellular granules by the platelets.
• This ultimately stimulates platelet aggregation.
3:Platelet
adhesion
• When the endothelium
is injured, platelets
adhere to and virtually
cover the exposed
collagen of the
subendothelium This
triggers a complex series
of chemical reactions,
resulting in platelet
activation.
4:Platelet
activation
›Receptors on the surface of the adhering platelets
are activated by the collagen of the underlying
connective tissue.
›This causes morphologic changes in
platelets and the release of platelet granules
containing chemical mediators, such as adenosine
diphosphate (ADP), thromboxane A2 ,
serotonin, platelet activation factor, and
thrombin .
›These signaling molecules bind to receptors in the
outer membrane of resting platelets circulating
nearby.
›These receptors function as sensors that are
activated by the signals sent from the adhering
platelets.
›The previously dormant platelets become activated
and start to aggregate.
These actions are mediated by several
messenger systems that ultimately result in
elevated levels of calcium and a decreased
concentration of cAMP within the platelet
5:Platelet aggregation
›The increase in cytosolic calcium
accompanying activation is due to a release of
sequestered stores within the platelet.
›This leads to
›1) the release of platelet granules containing
mediators, such as ADP and serotonin that activate
other platelets;
›2) activation of thromboxane A2 synthesis;
and
›3) activation of glycoprotein (GP) IIb/IIIa
receptors that bind fibrinogen and, ultimately,
regulate platelet–platelet interaction and thrombus
formation.
›Fibrinogen, a soluble plasma GP, simultaneously
binds to GP IIb/IIIa receptors on two separate
platelets, resulting in platelet cross-linking and
platelet aggregation.
›This leads to an avalanche of platelet
aggregation, because each activated platelet
can recruit other platelets
Formation of a
clot
8:Formation of Platelet fibrin
plug
›Local stimulation of the
coagulation cascade by tissue
factors released from the injured
tissue and by mediators on the
surface of platelets results in
the formation of thrombin
(factor IIa).
›In turn, thrombin, a serine
protease, catalyzes the hydrolysis of
fibrinogen to fibrin, which is
incorporated into the clot.
›Subsequent cross-linking of the
fibrin strands stabilizes the clot
and forms a hemostatic platelet–
fibrin plug
9:Fibrinolysis
›During clot formation, the
fibrinolytic pathway is
locally activated.
›Plasminogen is
enzymatically processed to
plasmin (fibrinolysin) by
plasminogen activators in the
tissue
›Plasmin limits the growth of
the clot and dissolves the
fibrin network as wounds
heal.
Platelet aggregation
inhibitors
›Platelet aggregation inhibitors decrease the formation of a
platelet-rich clot or decrease the action of chemical signals that
promote platelet aggregation .
›The platelet aggregation inhibitors inhibit cyclooxygenase-1
(COX-1) or block GP IIb/IIIa or ADP receptors, thereby interfering with
the signals that promote platelet aggregation.
›Because these agents have different mechanisms of actions,
synergistic or additive effects may be achieved when agents from
different classes are combined.
›These agents are beneficial in the prevention and treatment of
occlusive cardiovascular diseases, in the maintenance of vascular
grafts and arterial patency, and as adjuncts to thrombin inhibitors or
thrombolytic therapy in MI.
 ANTI
PLATELE
T
DRUGS:
Aspirin(Mechanism of action)
›Stimulation of platelets by thrombin, collagen, and ADP
results in activation of platelet membrane phospholipases that
liberate arachidonic acid from membrane phospholipids.
›Arachidonic acid is first converted to prostaglandin H2 by
COX-1 Prostaglandin H2 is further metabolized to thromboxane A2 ,
which is released into plasma.
›Thromboxane A2 promotes the aggregation process that is
essential for the rapid formation of a hemostatic plug.
›Aspirin inhibits thromboxane A2 synthesis by acetylation of a
serine residue on the active site of COX-1, thereby irreversibly
inactivating the enzyme.
›This shifts the balance of chemical mediators to favor the
antiaggregatory effects of prostacyclin, thereby preventing platelet
aggregation.
• ›The inhibitory effect is rapid, and aspirin-
induced suppression of thromboxane A2
and the resulting suppression of platelet
aggregation last for the life of the platelet,
which is approximately 7 to 10 days.
• ›Repeated administration of aspirin has a
cumulative effect on the function of
platelets.
• ›Aspirin is the only antiplatelet agent
that irreversibly inhibits platelet function
Therapeutic use:
• ›Aspirin is used in the prophylactic treatment
of transient cerebral ischemia, to reduce the
incidence of recurrent MI, and to decrease
mortality in the setting of primary and
secondary prevention of MI.
• ›Complete inactivation of platelets occurs
with 75 mg of aspirin given daily.
• ›The recommended dose of aspirin ranges
from 50 to 325 mg daily
Pharmacokinetics
:• ›When given orally, aspirin is absorbed by
passive diffusion and quickly hydrolyzed to
salicylic acid in the liver.
• ›Salicylic acid is further metabolized in the
liver, and some is excreted unchanged in the
urine.
• ›The half-life of aspirin ranges from 15 to
20 minutes and for salicylic acid is 3 to 12
hours.
Adverse effects:
• ›Higher doses of aspirin increase drug-related
toxicities as well as the probability that aspirin may
also inhibit prostacyclin production.
• ›Bleeding time is prolonged by aspirin treatment,
causing complications that include an increased
incidence of hemorrhagic stroke and gastrointestinal
(GI) bleeding, especially at higher doses of the drug.
• ›Nonsteroidal anti-inflammatory drugs, such as
ibuprofen, inhibit COX-1 by transiently competing at
the catalytic site.
Adverse effects:
• ›Ibuprofen, if taken within the 2 hours prior to aspirin,
can obstruct the access of aspirin to the serine residue
and, thereby, antagonize platelet inhibition by aspirin.
• ›Therefore, immediate release aspirin should be taken at
least 60 minutes before or at least 8 hours after
ibuprofen.
• ›Although celecoxib (a selective COX-2 inhibitor) does
not interfere with the antiaggregation activity of aspirin,
there is some evidence that it may contribute to
cardiovascular events by shifting the balance of
chemical mediators in favor of thromboxane A2 .
 BLOOD
COAGULATION:
Thrombin & Antithrombin
• Thrombin has central role in hemostasis (prevention
of blood loss from broken vessels.
• Thrombin ptoteolytically cleaves small peptide from
fibrinogen, polymerize it and form a fibrin clot.
• Thrombin is a platelet activator.
• Antithrombin is an endogenous anticoagulant
• It inactivates factor ΙΙa, IXa, Xa, XΙa and XΙΙa
• Defect in Antithrombin results in an increased risk of
thrombosis
Anti coagulants:
• The anticoagulant
drugs inhibit either the
action of the coagulation
fac tors (the thrombin
inhibitors, such as heparin
and heparin-related
agents) or interfere with
the synthesis of the
coagulation factors (the
vitamin K antag onists
such as warfarin).
• .It is strongly acidic because of the
presence of sulfate and carboxylic acid
groups
• Heparin is used in the prevention of venous
thrombosis and the treatment of a variety
of thrombotic dis eases, such as pulmonary
embolism and acute myocardial infarction.
Indirect Thrombin Inhibitors:
Parental Anticoagulant HEPARIN
• Unfractionated heparin (UFH) & Low-molecular –
weight heparin (LMWH) is the homogenous mixture
of sulfated mucopolysaccharides.
• Biological activity of heparin entirely depend upon
the endogenous anticoagulant antithrombin
• Antithrombin inhibits clotting factors by forming
stable complexes with them.
• Complex formation is very slow process, heparin
accelerates this process 1000-fold.
MECHANISM OF ACTION:
Therapeutic uses:
• Treating acute proximal deep vein thrombosis or pulmonary embolism.
• They are the anticoagulants of choice for treating pregnant women with
prosthetic heart valves or venous thromboembolism, because these agents do
not cross the placenta (due to their large size and negative charge).
• Heparin is used prophylactically to prevent postoperative venous thrombosis
in patients undergoing elective surgery (for example, hip replacement).
• It is used as Anticoagulant (treating and preventing blood clots caused by
certain medical conditions or procedures).
Pharmacokinetics:
• Heparin must be given
parenterally, either in a deep
subcutaneous site or
intravenously
• LMWHs are administered
subcutaneously.
• Metabolism: Occurs in the liver, renal, and
reticuloendothelial system.
• Half life of heparin is approximately 1.5
hours, whereas the half-life of the LMWHs
is two to four times longer than that of
heparin, ranging from around 3 to 7 hours.
• Patients with renal impairment, the dose should
be reduced to account for decreased renal
function.
Adverse Effects:
• Bleeding: The most common
adverse effect of heparin use is
hemorraghe, which can be treated
by protamine sulfate.
• Hypersensitivity reactions:
Heparin preparations are obtained
from porcine sources and, therefore,
may be antigenic. Possible adverse
reactions include chills, fever,
urticaria, and anaphylactic shock.
• Thrombocytopenia: This condition, in
which circulating blood contains an
abnormally small number of platelets,
is a common abnormality among
hospital patients receiving heparin.
Contraindications:
• Hypersensitive
Patients.
• Bleeding disorders.
• Alcoholic patients.
• Patients who had
recent surgery of
eye,brain and spinal
cord.
 The coumarin anticoagulants,
which include commonly used
warfarin and rarely used
dicumarol (bishydroxy coumarin),
Warfarin( owe their action to their ability to
antagonize the cofactor functions
Vitamin k of vitamin K.

Antagonis The only therapeutically relevant

t): coumarin anti coagulant is
warfarin. Initially used as a
rodenticide, warfarin is now
widely used clinically as an oral
anticoagulant.
MECHANIS
M OF
ACTION:
Mechanism of Action:
• protein coagulation factors ( Factors II, VII, IX, and X) require vitamin K as a
cofactor for their synthesis by the liver.
• These factors undergo vitamin K–dependent posttranslational modification,
where glutamic acid residues are carboxylated to form γ-carboxyglutamic acid
residues .
• The γ-carboxyglutamyl residues bind calcium ions, which are essential for
interaction between the coagulation factors and platelet membranes. In the
carboxylation reactions, the vitamin K–dependent carboxylase fixes CO2 to
form the new COOH group on glutamic acid.
• The reduced vitamin K cofactor is converted to vitamin K epoxide during the
reaction. Vitamin K is regenerated from the epoxide by vitamin K epoxide
reductase, the enzyme that is inhibited by warfarin.
THERAPEUTIC USES:

• Warfarin is used to prevent the progression or

recurrence of acute deep vein thrombosis or
pulmonary embolism.
• It is also used for the prevention of venous
thromboembolism during orthopedic or gynecologic
surgery.
• Prophylactically, it is used in patients with acute myocardial
infarction, prosthetic heart valves, and chronic atrial
fibrillation.
Pharmacokinetics:
• Warfarin is rapidly absorbed after oral administration
• The mean half-life of warfarin is approximately 40
hours, but this value is highly variable among
individuals.
• The products of warfarin metabolism, catalyzed by the CYP450
system, are inactive. After conjugation to glucuronic acid, they
are excreted in urine and feces. Agents that affect the
metabolism of warfarin may alter its therapeutic effects.
Adverse effects:
1.Bleeding disorders
2.Drug and other interactions
3.Disease states(neoplastic
disease, hyperlipidemia
and hypothyroidism, also
affect the patient’s
response to warfarin)
• C O N T R A I N D I C A T I O N S:

v Warfarin should never be used during

pregnancy, because it is teratogenic and can
cause abortion as well as birth defects (FDA
pregnancy category X). If anticoagulant
therapy is needed during pregnancy, heparin
or LMWH may be administered
REFERENCES:

• Lippincott's Illustrated Reviews:

Pharmacology,5 edition
• Rangs & Dale's Pharmacology Sixth
Edition