Download Anti-platelets

ANTI-PLATELETS
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
Anticoagulant are effective in preventing and treatment of thrombosis in the venous and
arterial systems.
Antiplatelet drugs are generally only considered for arterial and intra-cardiac thrombosis
as these thrombi are rich in platelets while thrombi/emboli in the venous system have a
relatively low platelet content.
Thrombolytic/fibrinolytic drugs have a direct action to dissolve existing thrombus and are
used for the acute treatment of thrombus, namely the treatment of acute myocardial
infarction, acute ischaemic stroke and massive PE.
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?
•
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
• 1 Vascular Phase
• 2 Platelet Phase
• 3 Coagulation Phase
• 4 Fibrinolytic Phase
Platelet Phase
• 1 Platelet adhesion
• 2 Platelet plug
• 3 Platelet aggregation
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
- Preventing bleeding from wounds
- Integrity and repair of the vessel wall
• 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
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
50-320mg/day
Pro - aggregation
• PGI2
Higher doses
Anti - aggregation
•
•
•
ASPIRINMOA-also rfrppt
In 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).
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 cyclo-oxygenase 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 in the bile;
a small amount is excreted in the urine
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:
MOArfrppt
Pharmacokinetic
• Both currently available ADP-receptor antagonists are thienopyridines that can be
administered orally, and absorption is approximately 80-90%
• Thienopyridines are prodrugs that must be activated in the liver
Uses
•
•
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
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
TiclodipineVs 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 antagonistsTiclopidine
• 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
Glycoprotein IIb/IIIa inhibitors
• Block final step in platelet aggregation induced by any agonist
• Abciximab
• Eptifibatide
• Tirofiban
GPIIb/IIIa Antagonist
MOA rfrppt
Glycoprotein IIB/IIIA receptors antagonists
• Platelet surface receptor, receptor for fibrinogen and von willebrandfactor,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.
GpIIb/IIIa inhibitors
1) 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
2) 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%)
3) Tirofiban
• Similar to eptifibatide
• Value in antiplatelet therapy after acute myocardial infarction is limited
• Used in conjunction with heparin
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 WORLD