Download Anti-platelet agents

Contents
• Introduction
• Classification
• Individual drugs
• Newer anti-platelet agents
• Summary
Introduction
• Normal homeostasis
• Maintenance of blood in a fluid, clot-free state in normal vessels; and
• Formation of haemostatic plug at a site of vascular injury.
• Opposite : Thrombosis
• Thrombi are lysed and blood is made fluid by fibrinolytic system
Coagulation
Fibrinolysis
Antithrombotic drugs
Fibrinolytics
Antithrombotic drugs
Fibrinolytics
Antithrombotic drugs
Fibrinolytics
Antithrombotic drugs
Fibrinolytics
Thrombosis
• Arterial Thrombosis :
• Adherence of platelets to arterial walls - White in color - Often associated
with MI, stroke and ischemia
• Venous Thrombosis :
• Develops in areas of stagnated blood flow (deep vein thrombosis), Red in
color- Associated with Congestive Heart Failure, Cancer, Surgery.
HOW PLAQUES ARE
FORMED?
Pathophysiology of the Thrombus
Blood Vessel
Endothelium
Subendothelium
INJURY
Vasoconstriction
Collagen
VWF
Platelet Adhesion
& Secretion
Tissue Factor
Coagulation Cascade
Thrombin
Platelet aggregation
Fibrin
Haemostatic plug
• Both hemostasis and thrombosis are regulated by three general
components
•The vascular wall,
•Platelets, and
•The coagulation cascade
HAEMOSTASISCessation of blood loss from damaged blood
Vascular Phase
Platelet Phase
Coagulation Phase
Vascular Phase
Vasoconstriction
Exposure to
tissues activate
Tissue factor and
initiate
coagulation
Tissue Factor
Platelet Phase
WHAT ARE PLATELETS ?
White, discoid
Smallest element of flowing blood
• 1 - 2 microns diameter
Lipid bilayer membrane
Normal range 150000 – 450000 microlitre blood
Formed from cytoplasm of megakaryocytes
No nucleus
Normal Function of Platelets
Haemostasis
Integrity
and repair
of the
vessel wall
Preventing
bleeding
from
wounds
• Receptors on platelets:
•
•
•
•
•
GpIa/IIa: receptors for collagen
GpIb: receptor for vWF
GpIIb/IIIa: receptor for fibrinogen
P2Y1/P2Y12: purinergic receptors for ADP
PAR1/PAR4: protease activated receptors for thrombin (IIa)
Basic concepts
• PGI2- inhibit platelet aggregation
• TXA2- platelet aggregation
• Elevated c-AMP- inhibit platelet aggregation & vice versa
• ADP receptors(P2Y1,P2Y2)-changes shape & platelet aggregation
• GPIIb/IIIa receptors- binds fibrinogen & platelets
• 5-HT-vasocostriction
• Collagen,Thrombin- platelet aggregation agonist
• Platelets provide the initial hemostatic plug at sites of vascular injury
• They also participate in pathological thromboses that lead to
myocardial infarction, stroke, and peripheral vascular thromboses
PLATELET AGGREGATORS
Collagen
Von willebrand factor
ADP
Thromboxane A2
Stress
Thrombin
The role of platelets
Platelet Activation Pathways
Collagen
Thrombin
Epinephrine
ADP
Arachidonic
acid
TxA2
GP IIb/IIIa
The role of platelets
The role of platelets
The role of platelets
Platelet adhesion and aggregation
Platelet-fibrin clot
Damaged blood vessel
Activation of platelets
Release of collagen
Arachidonic acid
Release of thrombin
Release of
ADP
COX
Cyclic endperoxidase
Activates P2Y1
Gq
Release of TXA2
Gi
Changes in platelet shape
inhibits adenylcyclase,
Increases phospoinositol
Activation of glycoprotein IIB/IIIA receptors
Fibrinogen
fibrin
decrease CAMP ?
PGI 2- (Prostacyclins)
Naturally occurring potent vasodilator and inhibitor of platelet
aggregation.
Produced by vessel walls, also present in brain ,gut and kidney.
Formed from PG endperoxidase by the action of COX
Inhibit platelet aggregation by stimulating adenylcyclase increasing
cyclic AMP levels in platelets.
Prostacyclins causes hypotension , tachycardia ,headache. intense facial
flushing
Very unstable ,1/2 life of 3 mins.
Prostacyclins (Epoprostananol)-used during haemodialysis.
Antiplatelet drugs
(Classification)
• TXA2 synthesis inhibitor:
• Low dose aspirin
• Phosphodiesterase inhibitor:
• Dipyridamole , cilostazole
• Thienopyridine derivatives (ADP antagonists):
• Ticlodipine, clopidogrel
• Gp-IIb/IIIa receptor antagonists
• Abciximab, eptifibatide, tirofiban
• Others
• PGI2
, daltroban, dazoxiben, clofibrate
ASPIRIN
• Aspirin blocks production of TxA2by acetylating a serine residue near the
active site of platelet cyclooxygenase-1 (COX-1)
• The action of aspirin on platelet COX-1 is permanent
• Anti-thrombotic dose is much lower than doses required for other
actions
• Higher doses do not improve efficacy
• Potentially less efficacious because of inhibition of prostacyclin
production
• Higher doses also increase toxicity, especially bleeding
TXA2
PGI2
• 50-320mg/day
• Pro aggregation
• Higher doses
• Anti aggregation
Aspirin
Mechanism Of Action
Mechanism Of Action
Mechanism Of Action
Mechanism Of Action
Mechanism Of Action
ASPIRIN• MOAIn platelets major COX product is TXA2 , a labile inducer of
platelet aggregation and potent vasoconstrictor.
Aspirin blocks production of TXA2 by covalently acetylating serine
residue near the active site of COX, this enzyme produces cyclic
endperoxidase precursor of TXA2.
Since platelets do not synthesize new proteins
hence the action of aspirin on platelets is
permanent (7-10 days).
For complete inactivation of platelet COX
dose of aspirin req. is 160 mg daily.
Reason—
Higher doses decrease efficacy of
aspirin as they inhibit production of
prostacyclins which is spared at low
doses. (75-150mg)
Higher doses also increase toxicity
esp.. Bleeding.
PHARMACOKINETICS
• Rapid absorption in the stomach and upper intestine,
• Peak plasma concentration in 15-20 minutes
• The peak inhibitory effect on platelet aggregation is apparent
approximately one hour post-administration
• Aspirin produces the irreversible inhibition of the enzyme cyclooxygenase and therefore causes irreversible inhibition of platelets for
the rest of their lifespan (7 days)
USE
• Secondary prevention of transient ischaemic attack (TIA), ischaemic
stroke and myocardial infarction
• Prevention of ischaemic events in patients with angina pectoris
• Prevention of coronary artery bypass graft (CABG) occlusion
MAJOR DRAWBACKS
• Risk of gastrointestinal adverse events (ulceration and bleeding)
• Allergic reactions
• Is not a very effective antithrombotic drug but is widely used because
of its ease of use
• Lack of response in some patients (aspirin resistance)
• The irreversible platelet inhibition
Phosphodiaster Inhibitors
• Dipyridamole
• Coronary vasodilator and relatively weak antiplatelet drug
MECHANISM
• Interferes with platelet function by increasing the cellular
concentration of cyclic AMP
• This effect is mediated by inhibition of cyclic nucleotide
phosphodiesterases and Blockade of uptake of adenosine
• cAMPpotentiates PGI2 and interferes with aggregation
PHARMACOKINETICS
• Incompletely absorbed from the gastrointestinal tract with peak plasma
concentration occuring about 75 minutes after oral administration
• More than 90% bound to plasma proteins
• A terminal half-life of 10 to 12 hours
• Metabolised in the liver
• Mainly
excreted
as
glucuronides
a small amount is excreted in the urine
in
the
bile;
USES
• Dipyridamole alone has little clinically significant effect
• Inhibits embolization from prosthetic heart valves when used in
combination with warfarin
• May potentiate the action of aspirin in preventing strokes in patients
with TIA,
• No additional benefit as combination with aspirin in preventing MI
MAJOR DRAWBACKS
• Is not a very effective antithrombotic drug
• Dipyridamole also has a vasodilatory effect and should be used with
caution in patients with severe coronary artery disease; chest pain may
be aggravated in patients with underlying coronary artery disease who
are receiving dipyridamole
ADP antagonist:
ADP-receptor antagonists – mechanism of
action
ADP-receptor antagonists – mechanism of
action
ADP-receptor antagonists – mechanism of
action
ADP-receptor antagonists – mechanism of
action
ADP-receptor antagonists – pharmacokinetics
• Both currently available ADP-receptor antagonists are thienopyridines
that can be administered orally, and absorption is approximately 8090%
• Thienopyridines are prodrugs that must be activated in the liver
ADP-receptor antagonists – major use
• Secondary prevention of ischaemic complications after myocardial
infarction, ischaemic stroke and established peripheral arterial
disease
• Secondary prevention of ischaemic complications in patients with
acute coronary syndrome (ACS) without ST-segment elevation
ADP-receptor antagonists – major drawbacks
• Clopidogrel is only slightly more effective than aspirin
• As with aspirin, clopidogrel binds irreversibly to platelets
• In some patients there is resistance to clopidogrel treatment
Ticlodipine & clopidogrel
• ADP antagonists, inhibit binding of ADP to its receptors irreversibly
• Also Inhibit fibrinogen induced platelet aggregation with out modifying
GPIIb/IIIa
• Synergistic action with aspirin
• Both are prodrugs have long duration of antiplatelet effect
• Clopidogrel a congener of ticlodipine is safer and better tolerated
Ticlodipine Vs clopidogrel
Ticlodipine
• Adverse effects:
– Diarrrhoea, vomiting, abdominal pain
– Headache, tinnitus, skin rash
– Bleeding, neutropenia, thrombocytopenia
• dose= 250 mg BD
Clopidogrel
• Adverse effects
– Bleeding most IMP
– Less bone marrow toxicity
– Diarrhoea, epigastric pain, rashes
• Dose = 75 mg OD
ADP antagonists- Ticlopidine
Ticlopidine blocks Gi coupled ADP receptors
It is a prodrug requires conversion to active form by Cyp450.
Rapid absorp. ,high bioavailability
Maximal inhibition of platelet inhibition it takes 8-11 days after starting therapy.
Dose-loading 500mg for rapid onset of action. Usual dose 250mgBD
AE- Nausea ,Vomiting, Diarrhea, Neutropenia, Thrombotic Thrombocytopenia
Uses-
Prevention cerebrovascular events, in 2ndary prevention of stroke
Unstable angina
Combination –Aspirin + ticlopidine---angioplasty, coronary artery stenting
Clopidogrel
Less toxic then ticlo. less incidence of leucopenia, thrombocytopenia.
Less used than Ticlopidine
MOA, PK profile same as Ticlopidine
Dose 75mg/day
Rest same as Ticlopidine.
GP IIb-IIIa Receptor
Final common
pathway to
platelet
aggregation
White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
Platelet GP IIb/IIIa Receptor in Vascular Injury: Adhesion
and Activation
Adhesion
GP IIb/IIIa
GP Ib-IX-V
Platelet
GP Ia/IIa
Endothelium
von Willebrand factor
Collagen
Activation
GP IIb/IIIa
Fibrinogen
(or von Willebrand
factor)
Platelet GP IIb/IIIa Receptor in Vascular Injury:
Aggregation
Fibrinogen
(or von Willebrand factor)
GP IIb/IIIa
Aggregation
`
Inhibition of
Platelet
Aggregation
GP IIb/IIIa
Receptor Inhibitor
Fibrinogen
Resting
Platelet
Receptors in
ligand-unreceptive
state
Activated Platelet
Receptors in ligandreceptive state
Aggregating
Platelets
GP IIb/IIIa receptors occupied by fibrinogen
which forms bridges between adjacent platelets
Glycoprotein IIb/IIIa inhibitors
• Block final step in platelet aggregation induced by any agonist
• Abciximab
• Eptifibatide
• Tirofiban
GPIIb/IIIa Antagonist
GPIIb/IIIa-receptor antagonists –
mechanism of action
GPIIb/IIIa-receptor antagonists –
mechanism of action
GPIIb/IIIa-receptor antagonists –
mechanism of action
GPIIb/IIIa-receptor antagonists –
mechanism of action
GPIIb/IIIa-receptor antagonists –
mechanism of action
Glycoprotein IIB/IIIA receptors antagonists
Platelet surface receptor, receptor for fibrinogen and von
willebrand factor,which anchors platelets to foreign
surface and each other thereby mediating aggregation.
Receptor is activated by TXA2, Collagen, and thrombin to
developbinding sites for its ligands.
Inhibition of binding to this receptor blocks platelet
aggregation induced by the agonist.
Abciximab
• Fab fragment of Chimeric monoclonal antibody against GP-IIb/IIIa.
• Used to prevent platelet aggregation in patients having PCI,
administered along with aspirin & heparin or LMW heparin
• Most common A/E is bleeding
• May cause thrombocytopenia, hypotension, bradycardia
• Non antigenic
• Dose: 0.25 mg/kg IV before PCI followed by 10 g/min for
12 hrs
Eptifibatide
• Cyclic peptide inhibitor of the fibrinogen binding site on GpIIb/IIIa
receptor
• Short duration of action: 6-12 hrs
• Given with aspirin and heparin
• Use:
• Acute coronary syndrome
• Angioplastic coronary interventions
• Adverse effects:
• Bleeding (10%)
• Thrombocytopenia (0.5-1%)
Tirofiban
• Similar to eptifibatide
• Value in antiplatelet therapy after acute myocardial infarction is
limited
• Used in conjunction with heparin
GpIIb/IIIa inhibitors
Features
Abciximab
Eptifibatide
Tirofiban
Description
Fab fragment of
humanized mouse
monoclonal antibody
Cyclical
heptapeptide
Nonpeptide
Specific for
GPIIb/IIIa
No
Yes
Yes
Plasma t1/2
Short
Long (2.5h)
Long (2.0h)
Platelet-bound
t1/2
Long (days)
Short (sec)
Short (sec)
Renal
clearance
No
Yes
Yes
PROSTACYCLINE ANALOGUES
• Ex are epoprostenol, iloprost
• These group of drugs block all pathway for platelet
activation.
• They also inhibits the expression of GPIIb/IIIa
receptor.
• Epoprostenol has a very short half life of 3 mins so it
has to be used by iv infusion.
• It causes headache and flushing due to vasodilation.
• iloprost is similar to epoprostenol but iloprost is
longer acting.
Newer anti-platelet agents
• Cangrelor
• Ticagrelor
• SCH530348
• E5555
THANK YOU
-PHARMA STREET