Anticoagulant drugs

Presented by: Mamona Waheed
Presented to : Prof. Dr Shoaib

Drugs that are useful in treating three important
dysfunctions of blood:
▪ Thrombosis
▪ Bleeding
▪ anemia

Thrombosis
▪ The formation of an unwanted clot within a blood
vessel is the most common abnormality of
hemostasis.
▪ Thrombotic disorders include acute myocardial
infarction, deep-vein thrombosis, pulmonary
embolism, and acute ischemic stroke. These are
treated with drugs such as anticoagulants and
fibrinolytics.

Thrombus VS. Embolus
▪ 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.

HAEMOSTASIS
The term haemostasis means prevention of
blood loss.
Haemostasis is the process of forming clots in
the walls of damaged blood vessels and
preventing blood loss, while maintaining blood in
a fluid state within the vascular system

Mechanism
1. Vascular spasm
2. Platelets reaction
3. Formation of platelet plug
3. Blood coagulation

Blood Coagulation
The clotting mechanism involves a cascade of
reactions in which clotting factors are activated.
Most of them are plasma proteins synthesized by
the liver (vitamin K is needed for the synthesis of
factor II, VII, IX and X). They are always present in
the plasma in an inactive form. When activated
they act as proteolytic enzymes which activate
other inactive enzymes. Several of these steps
require Ca++ and platelet phospholipid.

The ultimate step in clot formation is
the conversion of fibrinogen → fibrin.

Definition of
Anticoagulation
▪ Therapeutic interference ("blood-
thinning") with the clotting
mechanism of the blood to prevent
or treat thrombosis and embolism.

▪The anticoagulant drugs either
inhibit the action of the
coagulation factors (the
thrombin inhibitors, such as
heparin and heparin-related
agents) or interfere with the
synthesis of the coagulation
factors (the vitamin K
antagonists, such as warfarin).

▪The fibrinolytic system dissolves
intravascular clots as a result of
the action of plasmin, an
enzyme that digests fibrin.
Plasminogen, an inactive
precursor, is converted to
plasmin by cleavage of a single
peptide bond.

Plasmin
▪ Plasmin is a relatively nonspecific
protease,it digests fibrin clots and
other plasma proteins, including
several coagulation factors. Therapy
with thrombolytic drugs can dissolve
both pathological thrombi and fibrin
deposits at sites of vascular injury,
thus, such drugs also may promote
also hemorrhage.

Indications of Anticoagulant
Therapy
▪ Treatment and Prevention of Deep Venous
Thrombosis
▪ Pulmonary Emboli
▪ Prevention of stroke in patients with atrial
fibrillation, artificial heart valves, cardiac
thrombus.
▪ Ischaemic heart disease
▪ During procedures such as cardiac
catheterisation and apheresis.

NATURAL ANTICOAGULANT
MECHANISMS
▪ Platelet activation and coagulation normally
do not occur within an intact blood vessel.
Thrombosis is prevented by several regulatory
mechanisms that require a normal vascular
endothelium.
▪ Prostacyclin (prostaglandin I2; PGI2) is
synthesized by endothelial cells and inhibits
platelet aggregation and secretion

▪ Heparan sulfate proteoglycans synthesized by
endothelial cells stimulate the activity of
antithrombin.
▪ Protein C is a plasma zymogen that is homologous
to factors II, VII, IX, and X; its activity depends on the
binding of Ca2+ to g carboxyglutamate (Gla)
residues within its aminoterminal domain.
▪ Activated protein C, in combination with its
nonenzymatic Gla-containing cofactor (protein S),
degrades cofactors Va and VIIIa and thereby greatly
diminishes the activation of prothrombin and factor
X

▪ Protein C is activated by thrombin only in the
presence of thrombomodulin, an integral
membrane protein of endothelial cells. Like
antithrombin, protein C exerts an anticoagulant
effect in the vicinity of intact endothelial cells.
Tissue factor pathway inhibitor (TFPI) is found in
the lipoprotein fraction of plasma. When bound
to factor Xa, TFPI inhibits factor Xa and the
factor VIIa–tissue factor complex. By this
mechanism, factor Xa may regulate its own
production.

PARENTERALANTICOAGULANTS
SOURCE :
▪ Heparin is commonly extracted from porcine
intestinal mucosa or bovine lung. Despite the
heterogeneity in composition among
different commercial preparations of
heparin, their biological activities are similar
(~150 USP units/mg).

▪ The USP unit is
the quantity of
heparin that
prevents 1 mL of
citrated sheep
plasma from
clotting for 1 hour
after the addition
of 0.2 mL of 1%
CaCl2.

▪ Low-molecular-weight heparins (~ 4500 Da, or 15
monosaccharide units) are isolated from standard
heparin by gel filtration chromatography,
precipitation with ethanol, or partial
depolymerization with nitrous acid and other
chemical or enzymatic reagents.

▪Low-molecular-weight
heparins differ from standard
heparin and from each other
in their pharmacokinetic
properties and mechanism of
action

MECHANISM OF ACTION
▪Heparin catalyzes the inhibition of
several coagulation proteases by
antithrombin, a glycosylated, single-
chain polypeptide

▪Antithrombin is synthesized in the liver
and circulates in plasma inhibition occurs
when the protease attacks a specific Arg-
Ser peptide bond in the reactive site of
antithrombin and becomes trapped as a
stable 1:1 complex.

▪ Heparin increases the rate of the thrombin-
antithrombin reaction at least 1000-fold by serving as
a catalytic template to which both the inhibitor and
the protease bind. Binding of heparin also induces a
conformational change in antithrombin that makes
the reactive site more accessible to the protease.
Once thrombin has become bound to antithrombin,
the heparin molecule is released from the complex.

Miscellaneous
Pharmacological Effects
▪Prolong bleeding time.

CLINICAL USE
▪Treatment of venous thrombosis
and pulmonary embolism
because of its rapid onset of
action. An oral anticoagulant
usually is started concurrently,
and heparin is continued for at
least 4–5 days to allow the oral
anticoagulant to achieve its full
therapeutic effect.

Management of patients with
unstable angina or acute
myocardial infarction, during
and after coronary angioplasty
or stent placement, and during
surgery requiring
cardiopulmonary bypass.

TOXICITIES
▪ Bleeding Bleeding is the primary untoward effect
of heparin. the effect of heparin can be reversed
quickly by the slow intravenous infusion of
protamine sulfate, a mixture of basic polypeptides
that bind tightly to heparin and thereby neutralize
its anticoagulant effect. ~1 mg of protamine for
every 100 units of heparin

▪Anaphylactic reactions
▪Thrombocytopenia

Other Parenteral Anticoagulants
▪ Lepirudin (REFLUDAN) is a recombinant derivative (Leu1-Thr2-63-
desulfohirudin) of hirudin, a direct thrombin inhibitor present in
the salivary glands of the medicinal leech. It is a 65-amino-acid
protein that binds tightly to both the catalytic site and the
extended substrate recognition site of thrombin.

▪ Bivalirudin (ANGIOMAX) is a synthetic, 20-amino-
acid polypeptide that directly inhibits thrombin.

Binds reversibly to the catalytic site of thrombin.
Administered intravenously, it has an immediate onset of
action and a t1/2 of 40–50 minutes. Argatroban can be used
as an alternative to lepirudin for prophylaxis or treatment of
patients with or at risk of developing heparin-induced
thrombocytopenia.

MECHANISM OF ACTION
▪ The oral anticoagulants are antagonists of
vitamin K . Coagulation factors II, VII, IX,
and X and the anticoagulant proteins C
and S are synthesized mainly in the liver
and are biologically inactive unless 9–13
of the amino-terminal glutamate residues
are carboxylated to form the Ca2+-binding
g-carboxyglutamate (Gla) residues

▪. This reaction of the descarboxy
precursor protein requires CO2,
O2, and reduced vitamin K, and
is catalyzed by g-glutamyl
carboxylase in the rough
endoplasmic reticulum.
Carboxylation is directly coupled
to the oxidation of vitamin K to
its corresponding epoxide.

▪ The vitamin K cycle: G-glutamyl carboxylation of vitamin
K–dependent proteins. The enzyme g-glutamyl
carboxylase couples the oxidation of the reduced
hydroquinone form (KH2) of vitamin K1 or K2, to g-
carboxylation of Glu residues on vitamin K–dependent
proteins, generating the epoxide of vitamin K (KO) and
g-carboxyglutamate (Gla) residues in vitamin K–
dependent precursor proteins in the endoplasmic
reticulum. A 2,3-epoxide reductase regenerates vitamin
KH2 and is the warfarin-sensitive step. The R on the
vitamin K molecule represents a 20-carbon phytyl side
chain in vitamin K1 and a 5- to 65-carbon prenyl side
chain in vitamin K2.

▪ DOSAGE :
▪ The usual adult dose of warfarin
(COUMADIN) is 5 mg/day for 2–4
days, followed by 2–10 mg/day as
indicated by measurements of the
INR.

TOXICITIES
▪ Bleeding Bleeding is the major
toxicity of oral anticoagulant drugs.
The risk of bleeding increases with
the intensity and duration of
anticoagulant therapy, the use of
other medications that interfere with
hemostasis, and the presence of a
potential anatomical source of
bleeding.

Purple toe syndrome:
▪ A reversible, sometimes painful, bluish
discoloration of the plantar surfaces and sides of
the toes that blanches with pressure and fades
with elevation may develop 3–8 weeks after
initiation of therapy with warfarin

Clinical Use…
▪ To prevent the progression or recurrence of
acute deep vein thrombosis
▪ Pulmonary embolism following an initial
course of heparin.
▪ Orthopedic or gynecological surgery and
▪ In preventing systemic embolization in
patients with acute myocardial infarction,
prosthetic heart
▪ Valves, or chronic atrial fibrillation.

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