Anticoagulants

Ravindra Sajja
 Mechanisms of blood
coagulation
• Thrombogenesis (formation of blood
clot)

• Blood Coagulation
Thrombogenesis
Blood coagulation
• The main initiator of blood coagulation in
vivo is the tissue factor (TF)-factor VIIa
pathway. Tissue factor is a protein not
normally expressed in an active form
within vessels.
• The exposure of TF on damaged
endothelium binds TF to factor VII
• With tissue factor (TF), factor VII forms an
activated complex (VIIa-TF) that catalyzes
the activation of factor IX to factor IXa.
Activated factor XIa also catalyzes this
reaction.
• The cascade proceeds as shown, resulting
ultimately in the conversion of fibrinogen to
fibrin, an essential component of a
functional clot.
• Tissue factor pathway inhibitor (TFPI)
inhibits the catalytic action of the VIIa-TF
complex.
 Heparin
mechanism of action
• Heparin act by binding to antithrombin III to
cause a rapid anti coagulant effect.

Antithrombin III is a plasma protein that

inactivates thrombin and inhibit several
other clotting factors (eg:IIa, IXa, Xa) and
prevent abnormal clotting.
• Antithrombin III is referred to as heparin
cofactor.
 Heparin

In the absence of heparin, these reactions

are slow; in the presence of heparin, they
are accelerated 1000-fold.
• Heparin inhibits thrombin mediated
conversion of fibrinogen to fibrin.
• Heparin potentiates the activity of anti
thrombin III(X1000 times).
Heparin
 Heparin

• The combination of AT III with

unfractionated heparin increases
degradation of both factor Xa and
thrombin. Combination with fondaparinux
or LMWH more selectively increases
degradation of Xa.
 Types of heparin
LMWH
• Rapid anticoagulant HMWH
effect
• Less cost
• Onset of action is
• Administer I.V
immediate
• Decreased bioavailability
• Increase bioavalability
from the subcutaneous
from S.C injection.
site of injection,
• Can be given less
frequently (once/daily).
• Cause Less bleeding in
patients.
• Smaller risk of heparin
induced thrombocytopenia
• Smaller risk of
osteoporosis in long-term
use.
• Dalteparin, nadroparin,
enoxaparin and tinzaparin
• Heparin has pharmacokinetic limitations
not shared by LMWHs.
• Based on these pharmacokinetic
limitations, heparin therapy is usually
restricted to the hospital setting.
• Many patients now receive low-molecular-
weight heparin (LMWH) instead of
intravenous, continuous unfractionated
heparin for the treatment of deep venous
thrombosis (DVT).
 SIDE EFFECTS

• Hemorrhage
• Urticaria
• Increase loss of hair
• Thrombocytopenia
• Osteoporosis(longterm therapy)
• hyperkalemia, which occurs in 5 to 10% of
patients receiving heparin, and is the
result of heparin-induced aldosterone
suppression.
 USES

• unstable angina

• Deep vein thrombosis

•
• Pulmonary embolism
•
• Myocardial infarction
• Acute coronary syndrome
• Atrial fibrillation with embolization
• Prevention of clotting in arterial and
Cardiac surgery.
 ADME
• Administer S.C (or) I.V
• In blood heparin binds to many proteins
• Heparin inactivate by the liver enzyme
heparinase.
• T1/2 = 1.5hrs
• Contraindicated in I.M injection because of
hematoma (swelling under the skin).
 CONTRAINDICATION
• Should be avoided after surgery on the
eye and CNS.
• hemophilia,
• significant thrombocytopenia
• intracranial hemorrhage,
• infective endocarditis
 Therapy of heparin –
associated bleeding:
• Decrease (or) stop heparin therapy
•
• Administer protamine sulfate I.V
 Drug interactions
• heparin combine with oral anticoagulants,
salicylates, penicillins, or cephalosporins:
increased bleeding
•
• Decreased anticoagulation can occur if
heparin is combined with nitroglycerin
• Digitalis, tetracyclines, nicotine or
antihistamines may partially counteract the
anticoagulant action of heparin sodium.
 Warfarin
Mechanism of acton
• Warfarin is the most reliable member of
this group.
•
• It is a vitamin K antagonist.
•
• Vitamin K is necessary for the synthesis of
clotting factors (II, VII, IX, X) by liver.
•
• Warfarin inhibits the enzyme Vitamin K
epoxide reductase, which is necessary for the
conversion of inactive vitamin K epoxide (KO)
to active hydroquinone (KH2) form.

• Vitamin K1 or K2 is activated by reduction to

the hydroquinone form (KH2)
• Warfarin effects occurs 8 -12hrs after
administration of warfarin.
• The anticoagulant effect of warfarin is
antagonized by Vit K (aprox24hrs).
 Side effects

• Hemorrhage
•
• Urticaria
•
• Dermatitis
•
• Teratogenicity
•
• Hemolysis(large doses)
 Contraindication

• Should never used in pregnancy because

it is teratogenic and can cause abortion.
 Druginteractions

• 1) Phenylbutazone, Salicylates,
chloramphenicol, metronidazole, Clo-
trimaxazole potentiate anticoagulation by
inhibition of metabolism of warfarin.
•
• 2) Barbiturates, Griseofulvin, rifampin
stimulates the metabolism of warfarin.
 Uses

• Deep vein thrombosis

•
• Myocardial infarction
 ADME
• Well absorbed orally
•
• 99% bound to plasma albumin.
•
• Cross placental barrier
•
• Accumulate in the liver.
 Thrombolytic (or) Fibrinolytic
drugs:
•
• Eg: 1) Streptokinase
• 2) Alteplase
• 3) Anistreplase
• 4) Urokinase
• 5) Reteplase
• 6) Tenecteplase
• Plasminogen is present in plasma as an
inactive form of the proteolytic enzyme
Plasmin
• Plasminogen is activated by anumber of
agents known as plasminogen activators
• Plasminogen activates convert the
plasminogen to the active enzyme plasmin
•
• The enzyme plasmin is capable of
digesting many proteins including fibrin,
fibrinogen, and factors V and VII.
 Streptokinase

• It is a protein synthesized by streptococci

that combines with the proactivator
plasminogen.
•
• This enzymatic complex catalyse the
conversion of inactive plasminogen to
active plasmin.
•
• T1/2 = Less than 1/2hr
• Side effects:
Bleeding disorders
Hypersensitivity
•
•
• Uses:
DVT
 Anti fibrinolytics:
• Aminocaproic acid
• Tranexamic acid : Is an analog of
aminocaproic acid
• Aprotinin
• These drugs inhibit fibrinolysis and prevent
dissolution of clot. They act by inhibiting
plasminogen activation.
• Aminocaproic acid (I.V and oral) used to
control haemorrhage like surgical
bleeding.
• Other uses include hemophilia and
bleeding disorders.
 Anti - platelet drugs:

• 1)NSAID’s: Aspirin
•
• Mechanism of action:
Aspirin inhibit the synthesis of thrombaxane
A 2 from arachidonic acid in platelets by
inhibition of Cyclooxigenase-1 (COX-1).
Side effects:
• GI bleeding
• Tinitus
• CNS toxicity
•
Uses:
• Myocardial infarction
 Pharmacokinetics:
• Rapidly absorbed from the GIT
•
• First pass metabolism (hydrolysed to
salicylate)
•
• Onset of action- within 30min
•
• Peak time – 1hr
 Dipyridamole and Cilostazol:

• It is a vasodilator that inhibit platelet

function by inhibiting cyclic GMP
phoshodiesterae activity.
•
• Dipyridamole by itself has little or no
beneficial effect. Therefore therapeutic use
of this agent is primarily in combination
with aspirin to prevent cerebrovascular
ischemia.
• Cilaostazol is a newer phosphodiestarase
inhibitor that promotes vasodilation and
inhibition of platelet aggregation.
 ADP receptor
blockers
• Ticlopidine,
• Clopidogrel
Mechanism of action:
• Reduce platelet aggregation by inhibiting
the ADP path way of platelets
•
• Irreversibly blocking the ADP receptor on
platelets.
 Side effects:
Ticlopidine:
•
Bleeding (in 5% patients)
• Diarrhea (up to 20% of patients)
• Nausea, dyspepsia, leucopenia (1% of
patients)
•
Clopidogrel: fewer side effects than
ticlopidine.
• Rarely neutropenia
•
• Because of it’s superior side effect profile
clopidogrel is preferred over ticlopidine.
•
 GP IIb/IIIa receptor
blockers
•

• Abciximab
• Eptifibatide
• Tirofiban
 GPIIb/IIIa receptor
blocker
• It is a GPIIb/IIIa receptor blocker.
•
• Fibrinogen simultaneously binds to
GPIIb/IIIa receptors on 2 separate
platelets resulting in platelet aggregation.
•
• Tirofiban binding to GPllb/llla receptor on
platelet, inhibit the binding of fibrinogen
and prevent the platelet aggregation.
Side effects:
• Bleeding
•
Use:
• Acute coronary syndrome
 Thrombin inhibitors:
• Lepirudin
• It is a polypeptide and is highly specific
thrombin antagonist.
• Block the binding of thrombin to the
thrombin receptors.
•
• Side effects:
• Bleeding
Use:
• Heparin induced thrombocytopenia and
other thromboembolic disorders
•
• Half life = 1hr
 6)Serine Protease
Inhibitors:
•
• Eg: Aprotinin
• Inhibits fibrinolysis by inhibiting serine
protease (seprin).
• it also inhibit plasma plasmin-
streptokinase complex in patients who
have received that fibrinolytic agent.
•
• Reduce bleeding from many types of
surgery especially open heart and liver
transplantation.
• Use of this drug was associated with risk
of renal failure, heart attack, and stroke.
• The drug was removed from the market in
2007.