ANTITHROMBOTIC DRUGS

Sutomo Tanzil
Dept.of Pharmacology, Faculty of
Medicine, Sriwijaya University
Haemostasis & thrombosis
Haemostasis: the arrest of blood loss from damaged vessels.The
main phenomena are the platelet adhesion & activation, & blood
coagulation (fibrin formation).
Thrombosis: a pathological condition resulting from inappropriate
activation of haemostatic mechanisms within the blood vessel.
Venous thombosis is usually associated w/ stasis of blood. A
venous thrombus has a small platelet component & a large
component of fibrin.
Arterial thrombosis is usually associated w/ atherosclerosis, and
the thrombus has a large platelet component.
A portion of a thrombus may break away, travel as an embolus &
lodge downstream, causing ischaemia & infarction
 Blood coagulation (fibrin
formation)
The clotting system consists of a cascade of proteolytic enzymes & cofactors
Inactive precursors (zymogens) are activated in series
Thrombin(IIa), derived from prothrombin (II), converts soluble fibrinogen(I) to an
insoluble meshwork of fibrin in which blood cells are trapped, forming the clot.
2 pathways in the cascade: -the extrinsic pathway, which operates in vivo, &
the intrinsic/contact pathway, which operates in vitro.
Both pathways result in activation of factor X, which then converts prothrombin
to thrombin
Ca++ ions & a negatively charged phospholipid(PL) are essential for 3 steps,
namely the actions of : factor IXa on X, factor VIIa on X, factor Xa on II.
PL is provided by activated platelets adhering to damaged vessels
Some factors promote coagulation by binding to PL & a serine protease factor,
e.g.factor Va in the activation of X by IXa
Blood coagulation is controlled by enzyme inhibitors, e.g. antithrombin III, &
fibrinolysis.
 Vit K (procoagulant drug)
Vit K is essential for the formation of clotting factors II,
VII, IX & X. These are all glycoproteins w/ several -
carboxyglutamic acid (Gla) residues. Reduced form of
vit K (hydroquinone) is a cofactor in -carboxylation of
glutamic acid (glu) residues in each of factors II, VII, IX,
X. Gamma carboxylation occurs after the synthesis of
the chain & the carboxylase enzyme requires vit K as a
cofactor. Vit K is oxidised during the reaction. The -
carboxylated glutamic acid residues are essential for the
interaction of these factors w/ Ca++ & negatively charged
phospholipid.
Clinical use of anticoagulants
Heparin (often as LMWH) is used acutely for
short-term action
Warfarin is used for prolonged therapy
The prevention of : deep vein thrombosis or
recurrent pulmonary embolus; thrombosis &
embolisation in patients w/ AF; thrombosis on
prosthetic heart valves; clotting in extracorporeal
circulation (during haemodialysis/bypass-
surgery); cardiac events in patients w/ unstable
angina.
 Vascular endothelium in
haemostasis & thrombosis
Intravascular platelet activation & coagulation are prevented by
nonthrombogenic surface by virtue of surface heparan sulfate,
which is a cofactor for ATIII.
Endothelium also plays in haemostasis by synthesising von
Willebrand factors, tissue factor,& plasminogen activator
inhibitor-1 (PAI-1). PAI-1 is secreted in response to AIV. AIV
receptors which are present on endothelium, providing a link
between the RAS & thrombosis.
It also generates PGI2 & NO,converting ADP to adenosine ,
which inhibits platelet function, synthesising tPA, and expressing
thrombomodulin, a receptor for thrombin. After combination w/
thrombomodulin, thrombin activates protein C, a vit K-dependent
anticoagulant, which inactivates factors Va & VIIa.
 Injectable anticoagulants
(e.g.heparin, LMWHs)
Increase the rate of action of ATIII, a natural inhibitor that inactivates
Xa & thrombin
They act both in vivo or in vitro
Anticoagulant activity results from a unique pentasaccharide
sequence w/ high affinity for ATIII
The effect of heparin is monitored by the APTT (activated partial
thromboplastin time) & the dose is individualised.
LMWHs have the same effect on factor X as heparin but less effect
on thrombin. However , their anticoagulant effects are similar to
heparin
LMWHs are given s.c./i.v.-ly & the onset of action is rapid. A
standard dose (on a body weight basis) is given without the need for
monitoring or individual dose adjustment. Patients can administer
them at home.
 Factors that potentiate
warfarin
Liver disease interferes w/ the synthesis of clotting factors
Fever/thyrotoxicosis increase degradation of clotting factors
Cimetidine, imipramine, co-trimoxazole, chloramphenicol,
ciprofloxacin, metronidazole, & amiodarone inhibit warfarin
metabolism
NSAIDs, & carbenicillin inhibit platelet function
Aspirin increases the risk of bleeding if given during warfarin
therapy, although this combination can be used safely w/ careful
monitoring
Cephalosporins inhibit the reduction of vit K
Broadspectrum antibiotics & sulfonamides depress the intestinal
flora, which normally synthesise vit K
Factors that lessen the effect of
warfarin
Pregnancy: there is increased coagulation
factor synthesis
Hypothyroidism: reduced degradation of
coagulation factors
Vit K
Rifampicin, carbamazepine, barbiturates, &
griseofulvin induce hepatic P450 enzymes
Colestyramine reduces the absorption of
warfarin
 Reactions that happen when
platelets are activated
Adhesion following vascular damage (via von Willebrand factor bridging
between subendothelial macromolecules & glycoprotein (GP)Ib receptors
on the platelet surface).
Shape change (from smooth discs to spiny spheres w/ pseudopodia)
Secretion of the granule contents such as ADP & 5-HT, & coagulation
factors & growth factors such as platelet-derived growth factor)
Biosynthesis of PAF & TXA2
Aggregation, promoted by various agonists (collagen, thrombin, ADP &
TXA2) acting on specific receptors on the platelet surface. Activation by
agonists leads to expression of GPIIb/IIIa receptors which bind fibrinogen &
this links adjacent platelets sticking them together (aggregation)
Exposure of acidic PL on the platelet outer surface, promo-ting thrombin
formation
 Antiplatelet drugs
Aspirin
Dipyridamole
Thienopyridine derivatives (ticlopidine,
clopidogrel)
GP IIb/IIIa receptor antagonists
(abciximab)
Epoprostenol (PGI2)
 Targets for platelet inhibitory
drugs
Inhibition of Pg synthesis (aspirin)
Inhibition of ADP-induced platelet
aggregation(clopidogrel, ticlopidine)
Blockade of GP IIb/IIIa receptors on
platelet (abciximab, tirofiban, &
eptifibatide)
Dipyridamole & cilostazol are additional
antiplatelet drugs
 Aspirin
Alters the balance between TXA2 & PGI2
Mainly inactivates COX-1 by irreversible acetylation.
Reduces both TXA2 & PGI2 synthesis . However,TXA2 synthesis does not
recover until the affected cohort of platelets is replaced in 7-10 days.
Higher doses are needed to inhibits COX in the vascular endothelium than
in platelets,because platelets are exposed to aspirin in the portal blood,
whereas systemic vasculature is partly protected by presystemic
metabolism of aspirin by esterases in the liver. Consequently, low doses of
aspirin decrease the synthesis of TXA2 without drastically reducing PGI2
synthesis.
Other NSAIDs also inhibit COX but have a shorter duration of inhibitory
action because they cannot acetylate COX, so that their action is reversible.
 Dipyridamole
In clinical trials, dipyridamole reduced the risk of
stroke & death in patients w/ a history of
ischaemic stroke or TIA by around 15%
The beneficial effects of aspirin & dipyri-damole
were additive
Headache is the commonest adverse effect of
dipyridamole, but unlike aspirin, it causes no
excess risk of bleeding
 Cilostazol
A newer PDE inhibitor that promotes
vasodilation & inhibition of platelet
aggregation.
It is used primarily to treat intermittent
claudication
 Ticlopidine
It inhibits ADP-dependent aggregation
Slow onset of action, taking 3-7 days to reach
maximal effect, & it works through an active
metabolite
Its efficacy in reducing stroke is similar to that of
aspirin but idiosyncratic unwanted effects,
including severe blood dyscrasias (especially
neutropenia), have limited its long-term use
 Clopidogrel
Structurally related to ticlopidine & also inhibits ADP-
induced aggregation through an active metabolite.
Like ticlopidine, it can cause rash or diarrhoea, but
neutropenia is no more common than w/ aspirin.
In one large trial, clopidogrel was slightly more effective
than aspirin (325 mg/day) in reducing a composite
outcome of ischaemic stroke, myocardial infarction or
vascular death.
The effects of clopidogrel and aspirin are additive in
reducing major vascular events in patients w/ acute
coronary syndrome.
GP IIb/IIIa receptor antagonists
The IIb/IIIa complex function as a receptor
mainly for fibrinogen & von Willebrand factor.
Activation of this receptor complex is the final
common pathway for platelet aggregation.
Abciximab is a MAB directed against the GP
IIb/IIIa complex. It is approved for use in
percutaneous coronary intervention & in acute
coronary syndromes.
Eptifibatide & tirofiban inhibit ligand binding to
the GP IIb/IIIa receptor by their occupancy of the
receptor.
 Clinical uses of antiplatelet
drugs
The main drug is aspirin. Other drugs w/ different
actions (e.g.dipyridamole, clopidogrel) can be additive
in their effects. Uses mainly relate to arterial thrombus
(AMI, post MI,angina,intermittent
claudication),CABG,PTCA, unstable angina,TIA,
thrombotic stroke, AF .
Epoprostenol(PGI2) is sometimes administered
parenterally to prevent thrombosis during haemodialysis
in patients in whom heparin is contra-indicated.
 Fibrinolysis (Thrombolysis)
When coagulation system activated,the fibrinolytic system is also set
in motion by tPA, urokinase-type plasminogen activator (uPA),
kallikrein & neutrophil elastase.
Plasminogen is deposited on the fibrin strands within a thrombus.
Plasminogen activators diffuse into throm-bus & cleave plasminogen
to release plasmin.
Plasmin is formed locally & acts on the fibrin mesh-work, generating
fibrin degradation products & lysing the clot. Its action localised to
the clot because plasminogen activators are effective mainly on
plasminogen adsorbed to fibrin. Any plasmin that escapes into the
circulation is inactivated by plasmin inhibitors, including PAI-1, which
protect us from digesting ourselves from within.
Fibrinolysis and drugs modifying
fibrinolysis
A fibrinolytic cascade is initiated concomittantly w/ the
coagulation cascade, resulting in the formation of
plasmin within the coagulum, which digests fibrin.
Most agents that promote the formation of plasmin from
its precursor plasminogen (e.g. streptokinase, & tPA
such as alteplase, duteplase & reteplase) are given by
infusion.Reteplase can also be given as a bolus
injection.
Some drugs (e.g.tranexamic acid, aprotinin) inhibit
fibrinolysis.
 Streptokinase
a protein extracted from culture of strep-
tococci,which activates plasminogen
Infused intravenously, streptokinase re-duces
mortality in AMI & this beneficial effect is additive
w/ aspirin.
Its action is blocked by antistreptococcal
antibodies, which appear about 4 days or more
after the initial dose. At least 1 year must elapse
before it is used again.
 Alteplase & Duteplase
Both are recombinant tPA
They are more active on fibrin bound
plasminogen than on plasma plasminogen & are
said to be clot selective.
Recombinant tPA is not antigenic & can be used
in patients likely to have antibodies to
streptokinase. Because of their short t1/2, they
must be given as i.v.infusions.
Reteplase is similar but has a longer t1/2,
allowing for bolus administration
 Unwanted effects &
contraindications
The main hazard is bleeding,including GI
haemorrhage & stroke. If serious,this can be
treated w/ tranexamic acid, fresh plas-ma or
coagulation factors.
Streptokinase & anistreplase can cause allergic
reactions
Contraindications are active internal bleeding,
haemorrhagic CVD, bleeding diatheses,
pregnancy, uncontrolled hypertension, invasive
procedures in which haemostasis is important, &
recent trauma.
Clinical uses of fibrinolytic drugs
The main drugs are streptokinase & tPA
(e.g. tenecteplase)
The main use is in AMI, within 12 hrs of
onset (the earlier the better!)
Other uses include :-acute throm-botic
stroke within 3 hrs of onset (tPA) in
selected patients;-clearing thrombosed
shunts & cannulae; -acute arterial
thromboembolism.
 References
Katzung,B.G.(2007). Basic And Clinical
Pharmacology, 10th Edition, The McGraw-
Hill Companies,Inc. ,International Edition,
Singapore.
Rang,H.P.;Dale,M.M.et al.(2003).
Pharmacology,5th Edition, Churchill
Livingstone, Bath Press,UK.