ANTIPLATELETS.

ANTIPLATELETS

Contents Introduction Classification Individual drugs
Newer anti-platelet agents Summary

Introduction Normal homeostasis Opposite : Thrombosis
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 Normal hemostasis is the result of a set of well-regulated processes that accomplish two important functions: (1) They maintain blood in a fluid, clot-free state in normal vessels; and (2) They are poised to induce a rapid and localized hemostatic plug at a site of vascular injury. thrombosis; it can be considered an inappropriate activation of normal hemostatic processes

Coagulation Fibrinolysis

Antithrombotic drugs Fibrinolytics Antithrombotic drugs
There are three main classes of antithrombotic drugs Anticoagulants Antiplatelets Thrombolytic or fibrinolytic drugs. Antiplatelet and anticoagulant drugs inhibit platelet activation and aggregation, and the coagulation process respectively and can therefore be administered acutely to prevent the initial formation of blood clots (thrombi) in patients with recognised risk factors (primary prevention) and chronically to treat and prevent recurrence of thrombi and their associated complications (secondary prevention). Thrombolytic or fibrinolytic drugs act by dissolving existing thrombi or emboli and therefore only play a role in the acute treatment of thrombosis. Fibrinolytics September 2007

Antithrombotic drugs Antithrombotic drugs Fibrinolytics September 2007

Thrombosis Arterial Thrombosis : Venous 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

Haemostatic plug Collagen VWF Vaso- constriction Platelet Adhesion
Blood Vessel Endothelium Subendothelium INJURY Collagen VWF Tissue Factor Vaso- constriction Platelet Adhesion & Secretion Coagulation Cascade Thrombin Platelet aggregation Fibrin Haemostatic plug

The coagulation cascade
Both hemostasis and thrombosis are regulated by three general components The vascular wall, Platelets, and The coagulation cascade

HAEMOSTASIS- Cessation of blood loss from damaged blood
Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic Phase

Exposure to tissues activate Tissue factor and initiate coagulation
Vascular Phase Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulation Tissue Factor

Platelet Phase Platelet adhesion Platelet plug Platelet aggregation

Platelets play a central role in the development of thrombi and subsequent ischemic events. The process of platelet-mediated thrombus formation involves adhesion, activation, and aggregation. Within seconds of injury, platelets adhere to collagen fibrils through glycoprotein (GP) Ia/IIa receptors. An adhesive glycoprotein, von Willebrand factor (vWF) allows platelets to stay attached to the subendothelial vessel wall (via GP Ib) despite high shear forces. Following adhesion, platelets are activated to secrete a variety of agonists including thrombin, serotonin, adenosine diphosphate (ADP), and thromboxane A2 (TXA2). These agonists, which further augment the platelet activation process, bind to specific receptor sites on the platelets to activate the GP IIb/IIIa receptor complex, the final common pathway to platelet aggregation. Once activated, the GP IIb/IIIa receptor undergoes a conformational change that enables it to bind with fibrinogen.[1,2] Handin RI. Bleeding and thrombosis. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine. Vol 1. 14th ed. New York, NY: McGraw-Hill; 1998: Schafer AI. Antiplatelet therapy. Am J Med. 1996;101:

WHAT ARE PLATELETS ? White, discoid Smallest element of flowing blood
1 - 2 microns diameter Lipid bilayer membrane Normal range – 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 As slide

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 Antithrombotic drugs
Following vascular injury, von Willebrand factor binds to collagen in the exposed subendothelium at the site of injury. The other site of the “rod-formed” von Willebrand factor binds to the platelet receptor GPIb and platelets are thereby anchored to the site of the injured entothelium. This is called adhesion. September 2007

Platelet Activation Pathways
Collagen Thrombin Epinephrine ADP Arachidonic acid TxA2 GP IIb/IIIa

Following adhesion, agonists such as collagen, thrombin, adenosine diphosphate (ADP), and thromboxane A2 activate platelets by binding to their respective platelet receptors. September 2007

As a result of agonist binding, platelets undergo a shape change and new structures such as phospholipids and GPIIb/IIIa receptors are exposed on the cell membrane. This is called activation. September 2007

The third step of platelet response is aggregation. After activation, fibrinogen binds to GPIIb/IIIa to connect platelets together into a loose platelet plug. September 2007

Platelet adhesion and aggregation
Platelets first adhere to macromolecules in the subendothelial regions of the injured blood vessel, where they become activated. Adherent platelets release substances that activate nearby platelets, thereby recruiting them to the site of injury. Activated platelets then aggregate to form the primary hemostatic plug Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2(prostacyclin, PGI2), synthesized by endothelial cells, inhibits platelet activation.

Platelet-fibrin clot

Release of ADP Release of collagen Activation of platelets
Damaged blood vessel Release of collagen Activation of platelets Arachidonic acid Release of thrombin Release of ADP COX Cyclic endperoxidase Activates P2Y1 Gq Gi Changes in platelet shape Release of TXA2 inhibits adenylcyclase, Increases phospoinositol decrease CAMP ? Activation of glycoprotein IIB/IIIA receptors Fibrinogen fibrin

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 PGI2 (epoprostenol) Daltroban: txa2 receptor inhibitor Dazoxiben: thromboxane synthesis inhibitir Clofibrate Dextran 70 Nitric oxide

The mechanism of action of clopidogrel is similar to that of ticlopidine but different from that of aspirin.[1] Both clopidogrel and ticlopidine require biotransformation for their pharmacologic activity. Clopidogrel is a potent, noncompetitive inhibitor of ADP-induced platelet aggregation. Clopidogrel inhibits the binding of ADP to platelet membrane receptors. The effect of clopidogrel on ADP binding is irreversible[2] and lasts for the duration of platelet life, about 7 to 10 days. The inhibition is also specific and does not significantly affect cyclooxygenase or arachidonic acid metabolism.[1] Both low- and high-affinity ADP receptors are present on platelets, and the active metabolite of clopidogrel binds to the low-affinity receptors.[1] ADP binding to this site is necessary for activation of the GP IIb/IIIa receptor, which is the binding site for fibrinogen. Fibrinogen links different platelets together to form the platelet aggregate.[3] Clopidogrel thus ultimately inhibits the activation of the GP IIb/IIIa receptor and its binding with fibrinogen.[3] Aspirin inhibits the cyclooxygenase enzyme, preventing the production of prostaglandin and thromboxane A2 (TXA2) from arachidonic acid.[3] TXA2 activates the GP IIb/IIIa binding site on the platelet, allowing fibrinogen to bind. Aspirin also exerts its effects on other parts of the body system.[3] Paradoxically, aspirin blocks synthesis of prostacyclin by endothelial cells, resulting in an effect that promotes platelet aggregation.[3] Dipyridamole has been suggested to act as an antiplatelet drug by several possible mechanisms. It directly stimulates prostacyclin synthesis, potentiates the platelet inhibitory actions of prostacyclin, and inhibits phosphodiesterase to raise platelet cyclic AMP (cAMP) levels. However, these effects may not occur at therapeutic levels of the drug; hence the mechanism of action of dipyridamole remains to be elucidated.[3] Schrör K. The basic pharmacology of ticlopidine and clopidogrel. Platelets. 1993;4: Plavix® (clopidogrel bisulfate) Prescribing Information. Schafer AI. Antiplatelet therapy. Am J Med. 1996;101:

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 Because platelets do not synthesize new proteins, the action of aspirin on platelet COX-1 is permanent, lasting for the life of the platelet (7-10 days)

TXA2 PGI2 50-320mg/day Pro - aggregation Higher doses
Anti - aggregation The unique sensitivity of platelets to inhibition by such low doses of aspirin is related to their presystemic inhibition in the portal circulation before aspirin is deacetylated to salicylate on first pass through the liver (Pedersen and FitzGerald, 1984). In contrast to aspirin, salicylic acid has no acetylating capacity

Aspirin Acetylates and inhibits enzyme cox1 and tx synthetase – inactivating them irreversibly because platelets are exposed to aspirin in portal circulation before it is deacetylated , during first pass in liver and platelets cannot synthesize fresh enzyme as they do not have nuclei, TXA2 is supressed at very low doses and till fresh platelets are formed, thus aspirin induced polongation of bleeding lasts fot 5-7 days. Effect of daily dose cumulates and it has been shown that dose as low as 40 mg/day can have antiplatelet action mximal at 160 mgaspirin /day Aspirin also inhibits COX1 and PGI2 synthesis in vessel wall . But intimal cells can synthesize fresh enzym. Activity returns rapidly. It is possible that low doses mg per day or 300 mg biweekly , supress TXA2 formation selectively, whereas higher doses 900 mg/day may decrease both TXA2 and PGI2 production. Also inhibits release of adp from platelets and their sticking to one another

Mechanism Of Action Antithrombotic drugs
Thromboxane A2 is synthesized in platelets, from which it can be released. Thromboxane A2 causes vasoconstriction and is also a platelet agonist. September 2007

When thromboxane A2 binds to its platelet receptor… September 2007

Mechanism Of Action Antithrombotic drugs …the platelets are activated.
September 2007

Aspirin irreversibly inhibits cyclo-oxygenase (COX), an enzyme in platelets that is involved in the synthesis of thromboxane A2. September 2007

Thus, as aspirin downregulates the synthesis of the platelet agonist thromboxane A2, it will also inhibit platelet activation. September 2007

MOA- ASPIRIN- 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).

Higher doses also increase toxicity esp.. Bleeding.
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,
Antithrombotic drugs PHARMACOKINETICS Rapid absorption in the stomach and upper intestine, Peak plasma concentration in 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) Reference: Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287–94. September 2007

Antithrombotic drugs 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 September 2007

Antithrombotic drugs 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 September 2007

Phosphodiaster Inhibitors
Dipyridamole Coronary vasodilator and relatively weak antiplatelet drug So alone has little clinical significance but improves the response to warfarin, used with it for TE episodes in in patients with prosthetic heart valves. Dipyridamole alone has little effectbut in combination with warfarin or aspirin is effective As a vasodilator used during myocardial perfusion imaging (Thallium scanning) to dilate and evalutae arteries of patient with CAD DIP is

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 cAMP potentiates PGI2andinterfereswith aggregation

Antithrombotic drugs 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 September 2007

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
Antithrombotic drugs 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 September 2007

ADP antagonist:

ADP-receptor antagonists – mechanism of action
Antithrombotic drugs ADP-receptor antagonists – mechanism of action Ticlopidine and clopidogrel are ADP receptor antagonists, which bind to the receptor, but in contrast to the agonist ADP, they do not induce an intracellular response. September 2007

Antithrombotic drugs ADP-receptor antagonists – mechanism of action Ticlopidine and clopidogrel are irreversible inhibitors of the ADP receptor… September 2007

Antithrombotic drugs ADP-receptor antagonists – mechanism of action …and thereby prevent binding to the agonist. September 2007

Antithrombotic drugs ADP-receptor antagonists – mechanism of action In addition to preventing platelet aggregation induced by ADP, blockade of this receptor will also partly prevent aggregation intitated by other agonists, as ADP is released from all activated platelets irrespective of agonist. September 2007

ADP-receptor antagonists – pharmacokinetics
Antithrombotic drugs ADP-receptor antagonists – pharmacokinetics Both currently available ADP-receptor antagonists are thienopyridines that can be administered orally, and absorption is approximately % Thienopyridines are prodrugs that must be activated in the liver September 2007

ADP-receptor antagonists – major use
Antithrombotic drugs 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 September 2007

ADP-receptor antagonists – major drawbacks
Antithrombotic drugs 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 September 2007

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 First thieno pyridine derivative Ticlodipine is well absorbed orally , active metabolite in liver so long acting `half life after single dose is 8 hr and on repeated administration is 8 days

Ticlodipine Vs clopidogrel
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 Ticlodipine can cause mild to severe neutropenia, patients who are treated with ticlodipine must have a complete blood count, with white cell differential every 2 weeks from second week to third month of treatment. After 3 months CBC is required only when symptoms of infection

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.

Final common pathway to platelet aggregation
GP IIb-IIIa Receptor Final common pathway to platelet aggregation GP IIb-IIIa: the final common pathway to platelet aggregation Numerous agonists, including adenosine diphosphate (ADP), epinephrine, collagen, thrombin, and thromboxane A2 (TxA2), can activate platelets, but the final common pathway leading to platelet aggregation and thrombus formation is the expression of GP IIb-IIIa and the cross-linking of platelet receptors GP IIb-IIIa by fibrinogen molecules. White HD. Am J Cardiol ; 80(4A):2B-10B.

Fibrinogen (or von Willebrand factor)
Platelet GP IIb/IIIa Receptor in Vascular Injury: Adhesion and Activation GP IIb/IIIa Adhesion GP Ib-IX-V Platelet Endothelium GP Ia/IIa von Willebrand factor Fibrinogen (or von Willebrand factor) Vascular injury with ensuing platelet thrombus formation is the underlying pathophysiologic process in acute coronary syndromes (ACS) and in the development of complications of percutaneous coronary intervention (PCI). The injury may occur as a result of atherosclerotic plaque rupture or secondary to endothelial damage from balloon expansion or stent implantation. In either instance, the result is platelet adhesion to the damaged endothelium, leading to activation and aggregation. This process is mediated through the glycoprotein (GP) IIb/IIIa receptor and may be blocked by agents that bind to the receptor. Collagen GP IIb/IIIa Activation Coller B. Unstable angina. In: Braunwald E, ed. Inhibitors of Platelet Aggregation: GP IIb/IIIa Antagonists. Heart Disease, Update 4. Philadelphia, Pa: WB Saunders; 1995. Topol EJ, Byzova TV, Plow EF. Platelet GP IIb-IIIa blockers. Lancet.1999;353:

Platelet GP IIb/IIIa Receptor in Vascular Injury: Aggregation
Fibrinogen (or von Willebrand factor) GP IIb/IIIa Aggregation Platelet activation causes changes in the shape of platelets and conformational changes in GP IIb/IIIa receptors, transforming the receptors from a ligand-unreceptive to a ligand-receptive state. Ligand-receptive GP IIb/IIIa receptors bind fibrinogen molecules, which form bridges between adjacent platelets and facilitate platelet aggregation. Inhibitors of GP IIb/IIIa receptors also bind to GP IIb/IIIa receptors, blocking the binding of fibrinogen and thus preventing platelet aggregation. ` Coller B. Unstable angina. In: Braunwald E, ed. Inhibitors of Platelet Aggregation: GP IIb/IIIa Antagonists. Heart Disease, Update 4. Philadelphia, Pa: WB Saunders; 1995.

GP IIb/IIIa receptors occupied by fibrinogen
Inhibition of Platelet Aggregation GP IIb/IIIa Receptor Inhibitor Fibrinogen Activated Platelet Receptors in ligand- receptive state Resting Platelet Receptors in ligand-unreceptive state Our present state of understanding is shown on this slide: 1. The platelet is at first in a resting/inactive state. 2. Under the right stimulus, the platelet becomes active and the GP IIb/IIIa receptors become available for binding with fibrinogen. 3. Under normal conditions this results in crosslinking of the platelets by fibrinogen with platelet aggregation and clot formation. 4. Blockade of the GP IIb/IIIa receptor, shown in the upper right hand corner of the slide, now provides a therapeutic opportunity to prevent platelet aggregation by blocking this receptor and preventing crosslinking of the platelets with fibrinogen. 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
Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action The glycoprotein IIb/IIIa receptor is exposed on the platelet membrane after activation and is responsible for mediating platelet aggregation. September 2007

Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action Once activated, the receptor becomes functional and binds fibrinogen, leading to the formation of platelet aggregates. Glycoprotein IIb/IIIa receptors therefore mediate the final common pathway of platelet aggregation. September 2007

Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action GPIIb/IIIa antagonists hava a high affinity for the fibrinogen receptor… September 2007

Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action …and when binding is completed… September 2007

Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action …they will prevent fibrinogen from binding to the receptors. September 2007

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 Significantly prevent vessel restonosis, reinfarction and death

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 Plasma t1/2 Short Long (2.5h) Long (2.0h) Platelet-bound t1/2 Long (days) Short (sec) Renal clearance It also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells.

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

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