UDK: 615.273 medicinska revija ID BROJ: 209802252 medical review

Mihajlovi} I. MD-Medical Data 2014;6(3): 267-273 Aktuelne teme/ : THEIR PHYSIOLOGICAL AND Current topics PATHOPHYSIOLOGICAL ROLE AND THERAPEUTIC USE OF ANTIPLATELET DRUGS

TROMBOCITI: FIZIOLO[KA I PATOFIZIOLO[KA ULOGA

Correspondence to: I TERAPIJSKA PRIMENA Ivana Mihajlovi}, Dipl. farmaceut ANTIAGREGACIONIH LEKOVA Agencija za lekove i medicinska sredstva Republike Srbije Vojvode Stepe 458, 11152 Beograd Ivana Mihajlovi} Tel: 063/ 8480 369 E-mail: [email protected] Agencija za lekove i medicinska sredstva Republike Srbije

Abstract Key words Platelets play dual role in our body: physiological (beneficial) and pathophysiological (harmful) one. Physiologically, they prevent from the vascular wall injury, while Platelets, physiology, pathophysiology, pathologically participate in the formation causing thus very often severe cardio- antiplatelet drugs, therapeutic use vascular and cerebrovascular events. activation is initiated by G protein-coupled and the other surface receptors inolved in multistep process ending with recruitment of Klju~ne re~i additional platelets into a growing thrombus causing vascular obstruction. As a conse- Trombociti, fiziologija, patofiziologija, quence, efforts have been successfully made to discover potent antiplatelet agents, which antiagregacioni lekovi, terapijska prime- today belong to the most often prescribed drugs. They are used in primary and secondary na prevention of cardiovascular and cerebrovascular events. In the later case, they provide protection against possible subsequent events. They are used orally (long-term) or intra- venously (short-term acute use) and are in both cases clinically very effective. In primary prevention they are commonly used as monocomponents, but in secondary prevention more often as two-component preparations (e.g. plus dypiridamole and aspirin plus ). Out of 11 antiplatelet preparations marketed world wide, eight (78%) are available in our country. In order to be up-dated, novel parenteral preparations- abciximab and - should be added to the existing antiplatelet drugs in our country.

DISCOVERY, ORIGIN AND MORPHOLOGY the bloodstream and circulate for about 10 days before their OF PLATELETS removal, largely by the spleen. They circulate freely without adhesion to the vessel wall or aggregation with other (2) The first accurate and convincing description of platelets platelets . in journal Archiv für microscopische Anatomie in 1865. was Platelets play a crucial role in hemostasis. In circulation, published by German anatomist Max Schultze, as part of a they are not only the smallest blood cells, but also the light- study devoted mainly to white blood cells. He described est. Therefore they are pushed out from the center of flow- “spherules” much smaller than red blood cells that occasion- ing blood to the wall of the blood vessel. There they roll ally clump and may participate in collections of fibrous along the surface of the vessel wall, endothelium, which pre- material (1). vents anything from sticking to it. However, when there is an Platelets are derived from the cytoplasm of megakary- injury, platelets are the first to react. Stimulated, platelets oicytes, primarily located in the marrow. They are become spherical, extend pseudopods, and adhere to vessel small, disc-shaped cells without a nucleus, but contain walls and to each other (2). They clump onto fiber of the ves- megakaryocyte derived messenger RNA (mRNA) and the sel wall, providing the initial seal to prevent bleeding (3), ful- translational machinery needed for protein synthesis. filling thus their primary physiological role in our body. Usually measuring 1 to 2 µm in diameter. The mean platelet Platelets are composed of three principal components: count in children and adults is about 250x109/L, ranging membrane structures, microtubules, and granules (Fig. 1). from 150 to 400x109/L. Normally, a platelets are released to

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eration of A2 (TXA2), induction of a procoagulant surface, and activation of GPIIb/IIIa receptors (7). Profile of antiplatelet drugs Antiplatelet drugs act through a wide range of mechanisms, and they can be classified according to their mechanism of action. Drug classes include: ADP antagonists (), cyclooxygenase (COX-1) inhibitors (the only member of this class is aspirin), phosphodiesterase inhibitors, analogue of and GPIIb/IIIa inhibitors (Table 1):

Fig.1. Platelet structure available online (2) Table 1. Mechanism of action of antiplatelet drugs (8)

Drug Mechanism of action Platelet dysfunction due to congenital and acquired eti- Aspirin COX inhibitors ologies is one of the most common causes of bleeding Phosphodiesterase inhibitors encountered in clinical practice. Analogue of prostacyclin Function of platelets Clopidogrel ADP antagonists In a normal physiological state, platelets circulate with- out adhering to undisturbed vascular endothelium. Upon dis- ruption of the integrity of the vascular endothelium or alter- ation in the shear stress of the blood flow, platelets are “acti- Abciximab GP IIb/IIIa inhibitors vated”. Platelet activation plays a central role in both benign and pathological responses to vascular injury and thrombus Tirofiban formation. The process of transformation of inactivated Antiplatelet drugs protect against myocardial infarction, platelets into a well-formed platelet plug occurs along a con- stroke, cardiovascular death and other serious vascular tinuum, but may be divided into three steps: (1) adhesion, events in patients with a history of previous events or known (2) aggregation, and (3) secretion (4). risk facctors for cardiovascular disease. They decrease The primary function of platelets is to stop blood loss platelet aggregation and may inhibit thrombus formation in after tissue trauma and exposure of the subendothelial the arterial circulation, where have little matrix. Hemostasis and pathological thrombus formation are effect (9, 10). dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional Aspirin intracellular signals, and release of platelet proteins and inflammatory substances (5). Aspirin (acetylsalicylic acid) inhibits platelet aggrega- Platelets undergo morphological changes upon activa- tion and is used in the prevention of arterial and venous tion. Platelet shape changes from a disc to a spiny sphere thrombosis. It irreversibly inhibits cyclooxygenase in with multiple pseudopodial extensions. The contents of platelets and thereby blocks the formation of thromboxane (9, 4) platelet granules are secreted through the surface-connected A2, a potent vasoconstrictor and platelet aggregant . canalicular system, with adenosine diphosphate (ADP), fib- Since platelets lack the ability to synthesize new pro- rinogen, and factor V appearing on the platelet surface and teins, the effects persist for the life of the exposed platelets in the milieu immediately surrounding the platelet. (7-10 days). Acetylsalicylic acid may also inhibit production Recurrent episodes of platelet activation increases smooth of the platelet aggregation inhibitor, prostacyclin (6) muscle proliferation and may initiate atherosclerosis . (prostaglandin I2), by blood vessel endothelial cells; howev- As platelets are recruited to the area of blood vessel dam- er, inhibition of prostacyclin production is not permanent as age, they become activated by a range of agonists including endothelial cells can produce more cyclooxygenase to ADP, and , which interact with replace the non-functional enzyme (11). transmembrane receptors. Receptor stimulation results in G protein interactions, which enable activation of enzymes Dipyridamole involved in cellular metabolic pathways, in particular, phos- Dipyridamole inhibits phosphodiesterase, which inacti- phatidylinositol 3-kinase and phpspholipase C. Metabolic vates cyclic AMP (adenosine monophosphate). pathway activation results in the elevation of cytoplasmic Dipyridamole likely inhibits both adenosine deaminase calcium and phosphorylation of substrate proteins, which and phosphodiesterase, preventing the degradation of cAMP, bring about changes in the cytoskeleton, enabeling platelet an inhibitor of platelet function. This elevation in cAMP shape change and spreading, release of alpha- and dense- blocks the release of arachidonic acid from membrane phos- granular contents, stimulation of phospholipase A2 and lib-

Aktuelne teme/ Current topics Medicinska revija Medical review 269 pholipids and reduces thromboxane A2 activity. Dipy- aggregation induced by agonists other than ADP is also ridamole also directly stimulates the release of prostacyclin, inhibited by the active metabolite of ticlopidine. Ticlopidine which induces adenylate cyclase activity, thereby raising the is the oldest currently available (11, 16). intraplatelet concentration of cAMP and further inhibiting Prasugrel platelet aggregation. Because the effect is short-lastig, Prasugrel is an thienopyridine which inhibits ADP repeated dosing is required to inhibit platelet function for 24 receptors by irreversibly acting on the P2Y12 receptor on hours (9, 11). platelets. The active metabolite of prasugrel prevents bind- Aspirin, dipyridamole ing of adenosine diphosphate (ADP) to its platelet receptor, Dipyridamole alone has little antiplatelet effect. It is cur- impairing the ADP-mediated activation of the glycoprotein rently used in combination with aspirin in the prophylaxis of GPIIb/IIIa complex. Prasugrel is proposed to have a similar thromboembolic disorders (12) approved in our Country (13) mechanism of action to clopidogrel. Prasugrel is more effec- as Aggrenox® . tive than ticlopidine and clopidogrel at inhibiting the ADP receptor. Prasugrel is a novel platelet inhibitor (11, 17). Clopidigrel, aspirin (DuoPlavin®) It has been recently shown that the combination therapy Glycoprotein IIb/IIIa receptor blockers: abciximab, epti- with clopidogrel and aspirin provided greater protection fibatide and tirofiban against subsequent stroke than aspirin alone (14). The glycoprotein IIb/IIIa inhibitors are used parenterally in patients with acute coronary syndromes by specialists. Treprostinil This class of drugs is not used in an outpatient setting by Treprostinil is a synthetic analogue of prostacyclin, used non-specialists. Platelet membrane GPIIb/IIa receptors con- to treat pulmonary hypertension. The major pharmacologi- stitute the final common pathway of platelet aggregation; the cal actions of treprostinil are direct vasodilation of pul- integrin GPIIb/IIIa antagonists prevent cross-linking of monary and systemic arterial vascular beds and inhibition of platelets. Their action is independent of the aggregation- platelet aggregation (11). inducing stimulus (12). Thienopyridine derivatives Abciximab Abciximab is a humanised mouse fragment Clopidrogel, ticlopidine and prasugrel (Fab fragment of the chimeric human-murine monoclonal Clopidrogel and ticlopidine are thienopyridine deriva- antibody 7E3) with a high binding affinity for the glycopro- tives and metabolised in the liver to active compounds tein IIb/IIIa receptor, binds to the glycoprotein (GP) IIb/IIIa which covalently bind to the adenosine diphosphate (ADP) receptor of human platelets and inhibits platelet aggregation receptor on platelets and dramatically reduce platelet acti- by preventing the binding of fibrinogen, von Willebrand fac- vation (9,12,15). tor and other adhesive molecules (9,11,15). The active metabolite of clopidogrel prevents binding of Eptifibatide adenosine diphosphate (ADP) to its platelet receptor, impair- Eptifibatide mimics part of the structure of fibrinogen ing the ADP-mediated activation of the glycoprotein that interacts with the glycoprotein IIb/IIIa receptor and thus GPIIb/IIIa complex. It is proposed that the inhibition compete with ligand binding of fibrinogen to the glycopro- involves a defect in the mobilization from the storage sites tein IIb/IIIa receptor. The drug is always used combined of the platelet granules to the outer membrane. The drug with aspirin or clopidogrel. Synthetic cyclic hexapeptide specifically and irreversibly inhibits the P2Y12 subtype of that binds to platelet receptor glycoprotein (9,11,15,18). ADP receptor, which is important in aggregation of platelets and cross-linking by the protein fibrin. No direct interfer- Tirofiban ence occurs with the GPIIb/IIIa receptor. As the glycopro- Tirofiban is a reversible antagonist of fibrinogen binding tein GPIIb/IIIa complex is the major receptor for fibrinogen, to the GP IIb/IIIa receptor, the major platelet surface recep- its impaired activation prevents fibrinogen binding to tor involved in platelet aggregation. Platelet aggregation platelets and inhibits platelet aggregation. By blocking the inhibition is reversible following cessation of the infusion of amplification of platelet activation by released ADP, platelet tirofiban. It is a non-peptide reversible antagonist of the aggregation induced by agonists other than ADP is also platelet glycoprotein (GP) IIb/IIIa receptor (11,15). inhibited by the active metabolite of clopidogrel (11). Ticagrelor The active metabolite of ticlopidine prevents binding of Ticagrelor, cyclopentyltriazolopyrimidine, is a inhibitor adenosine diphosphate (ADP) to its platelet receptor, impair- of platelet activation and aggregation mediated by the P2Y ing the ADP-mediated activation of the glycoprotein 12 ADP-receptor (19). GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites THERAPEUTIC USE OF ANTIPLATELET of the platelet granules to the outer membrane. No direct DRUGS, CLINICAL EFFICACY interference occurs with the GPIIb/IIIa receptor. As the gly- coprotein GPIIb/IIIa complex is the major receptor for fib- Antiplatelet drugs can inhibit platelet adhesion, aggrega- rinogen, its impaired activation prevents fibrinogen binding tion, release and activation of platelets and with different to platelets and inhibits platelet aggregation. By blocking the mechanisms may be important in treatment. amplification of platelet activation by released ADP, platelet

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Table 2. Antiplatelet drugs - clinical use (11,15,16,19,20) Agent Route of Clinical use Absorbtion Biotransfor Half life Protein Volumen of Side effects administra- mation binding distribution tion Abciximab Solution intra- As an adjunct Rapidly. Most likely 10-30 min Bleeding, venous to percutaneous Platelet func- removed by hypoesthesia, coronary inter- tion recovers opsonization nausea, vention for the over about 48 via the reticu- hypotension, prevention of hours although loendothelial atrial fibrila- cardiac abciximab may system when tion, pleural ischemic com- remain in the bound to effusion or plications in circulation for platelets, or by pleurisy. patients under- 15 days or human going percuta- more in a antimurine anti- neous coronary platelet-bound body produc- intervention state. tion. and in patients with unstable angina not responding to conventional medical therapy when percuta- neous coronary intervention is planned within 24 hours.

Acetylsalicylic Oral In the preven- Rapid and com- Rapidly Approximately High (99.5%) Tinnitus, acid tion of arterial plete following hydrolyzed pri- 15 minutes to albumin abdominal pain, and venous oral administra- marily in the hypokalemia, thrombosis tion but may liver to salicylic hypoglycemia, vary according acid, which is pyrexia, hyper- to specific sali- conjugated with ventilation, cylate used, glycine (form- dysrhythmia, dosage form, ing salicyluric hypotension, and other fac- acid) and glu- hallucination, tors such as curonic acid renal failure, tablet dissolu- and excreted confusion, tion rate and largely in the seizure, coma, gastric or intra- urine. and death luminal pH. Clopidrogel Oral Reduce athero- At least 50% Hepatic, exten- Carboxylic acid 98% Vomiting (in sclerotic events based on uri- sive and rapid, derivative: 8 baboons), pros- such as nary excretion by hydrolysis hours (after sin- tration, difficult myocardial of clopidogrel- to the main cir- gle and multi- breathing, and infarction, related metabo- culating ple doses). gastrointestinal stroke, and vas- lites. metabolite, a Covalent bind- hemorrhage. cular death in carboxylic acid ing to platelets patients who derivative, has accounted have had a which accounts for 2% of radi- recent stroke, for approxi- olabeled clopi- recent MI, or mately 85% of dogrel with a have estab- the circulating half-life of 11 lished peripher- drug-related days. al vascular dis- compounds. A ease. glucuronic acid derivative of the carboxylic acid derivative has also been found in plas- ma and urine. Neither the par- ent compound nor the car- boxylic acid derivative has a platelet inhibit- ing effect.

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Agent Route of Clinical use Absorbtion Biotransfor Half life Protein Volumen of Side effects administra- mation binding distribution tion Dipyridamole Oral Combined 70% Hepatic 40 minutes 99% 1 to 2.5 L/kg Hypotension, with other if it occurs, is likely to be of drugs, such as short duration, , to but a vasopres- prevent throm- sor drug may bosis in be used if nec- patients with essary. valvular or vascular disor- ders. Dipyridamole is also used in myocardial perfusion imaging, as an antiplatelet agent, and in combination with aspirin for stroke pro- phylaxis. Eptifibatide Solution intra- Unstable angi- Antiplatelet The drug 2.5-2.8 hours 25% bound to 185-260 mL/kg Bleeding, venous na and non- effects persist appears to plasma proteins decrease in ST-segment- for about 4 undergo rapid platelet count elevation hours after and nonmeta- or thrombocy- myocardial stopping a bolic degrada- topenia, infarction. continuous tion in the uri- hypotension. Acute infusion. nary bladder ischemic after its elimi- Complications nation from of PCI plasma

Prasugrel Acute coro- Prasugrel is a The active nary syn- prodrug and is metabolite has dromes rapidly metab- an elimination planned for olized to a half-life of percutaneous pharmacologi- about 7 hours coronary inter- cally active (range 2-15 vention (PCI). metabolite and hours). inactive metabolites. Ticlopidine Oral To reduce the Greater than Metabolized Half-life fol- Reversibly GI hemor- risk of throm- 80%. Food extensively by lowing a sin- (98%) to plas- rhage, convul- botic stroke increases the liver; only gle 250-mg ma proteins, sions, (fatal or nonfa- absorption. trace amounts dose is mainly to hypothermia, tal) in patients of intact drug approximately serum albumin dyspnea, loss who have are detected in 7.9 hours in and lipopro- of equilibrium experienced the urine. At subjects 20 to teins. and abnormal stroke precur- least 20 43 years of gait. sors, and in metabolites age and 12.6 patients who have been hours in sub- have had a identified. It jects 65 to 76 completed has been pro- years of age. thrombotic posed that 1 or With repeated stroke. more active dosing (250 metabolites mg twice a may account day), half-life for ticlopi- is about 4 days dine's activity, in subjects 20 because ticlo- to 43 years of pidine itself is age and about an extremely 5 days in sub- weak platelet jects 65 to 76 aggregation years of age. inhibitor in vitro at the concentrations achieved in vivo.

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Agent Route of Clinical use Absorbtion Biotransfor Half life Protein Volumen of Side effects administra- mation binding distribution tion Tirofiban Solution intra- For treatment, After stopping Metabolism 2 hours 65% 22 to 42 L Bleeding, venous in combination an infusion, appears to be decrease in with , the antiplatelet limited platelet count of acute coro- effect persists or thrombocy- nary syn- for about 4 to topenia occurs drome, includ- 8 hours. occasionally, ing patients bradycardia, who are to be edema/swellin managed med- g or vasovagal ically and reactions, those undergo- pelvic pain, ing PTCA or leg pain and atherectomy. dizziness. Treprostinil Solution intra- For use as a Relatively Substantially Terminal elim- Approximately 14 L/70 kg Flushing, venous continuous rapid and com- metabolized ination half- 91% in in vitro headache, subcutaneous plete after sub- by the liver, life is approxi- concentrations hypotension, infusion or cutaneous but the precise mately 2 to 4 ranging from nausea, vomit- intravenous infusion. enzymes hours. Plasma 330 to 10,000 ing, and diar- infusion (for Absolute responsible are half-life is 34 µ/L. rhea. those not able bioavailability unknown. and 85 min- to tolerate a approximately utes for intra- subcutaneous 100%. venous and infusion) for subcutaneous the treatment infusion of the of pulmonary drug, respec- arterial hyper- tively. tension in patients with NYHA Class II-IV symp- toms to dimin- ish symptoms associated with exercise. Ticagrelor Oral To reduce the tmax of 1.5 h CYP3A4 is the The mean t½ 88 L Bleeding rate of throm- major enzyme is approxi- botic cardio- responsible for mately 7 hours vascular ticagrelor for ticagrelor events in metabolism and 9 hours patients with and the forma- for the active acute coronary tion of its metabolite syndrome major active (ASC) unsta- metabolite. ble angina, non-ST eleva- tion myocar- dial infarction, or ST eleva- tion myocar- dial infarction Table 3: Antiplatelet drugs registered for the use world-wide (20), Antiplatelet drugs approved for use in Serbia com- USA (7,21), Great Britain (10,22) and in Serbia (13) pared with some other countries Agent USA Great Britain Serbia MD1 In our country 8 medicines (two in combination with Abciximab + + - + aspirin) according to their International Nonproprietary Aspirin + + + + Names (INNs) are approved for use (Table 3). Aspirin, Table 3 shows that the number of antiplatelet drugs dipyridamole + + + + approved for the use in our country is less compared with the Clopidrogel + + + + rest of the world (20), USA (7, 21) and Great Britain (10, 22) Clopidogrel, aspirin - - + - (being 11 and nine: eight, amounted to 78% in relation to Dipyridamole + + - + world-wide and USA). This lag in the first place relates to Eptifibatide + + + + Prasugrel + + - + abciximab and tirofiban, two important antiplatelet drugs Ticlopidine + - + + used intravenously blocking GP IIb/IIIa receptor. They Ticagrelor ++ + + + decrease the incidence of thrombotic complications associ- Tirofiban + + - + ated with acute coronary syndromes. Therefore, they might Treprostinil + - + + be considered as the useful supplements to the existing Total 11 9 8 11 antiplatelet drugs in our country. 1 Sweetman, Martindale (20)

OriginalniAktuelne ~lanci/ teme/ Original Current articles topics Medicinska revija Medical review 273

Sa`etak Trombociti imaju dvostruku ulogu u na{em organizmu: fiziolo{ku (korisnu) i patolo{ku ({tetnu). Fiziolo{ka se ispoljava u spre~avanju krvarenja iz o{te}enog zida krvnog suda, dok se patolo{ka ogleda u njihovom u~e{}u u formiranju tromba koji ~esto predstavlja uzrok te{kih kardiovaskularnih i cerebrovaskularnih doga|aja. Aktivacija trombocita ini- cirana je udru`ivanjem G proteina i drugih receptora na povr{ini membrane trombocita. Ovaj proces zavr{ava se dodatnim nagomilavanjem trombocita u rastu}i tromb, koji izaziva vaskularnu opstrukciju. Iz tog razloga, radilo se na iznala`enju mo}nih antiagrega- cionih lekova, koji se danas nalaze u grupi naj~e{}e propisivanih lekova. Oni se koriste u primarnoj i sekundarnoj prevenciji kardiovaskularnih i cerebrovaskularnih doga|aja, i na taj na~in spre~avaju mogu}e komplikacije. Upotrebljavaju se oralno (dugotrajna upotreba) ili intravenozno (kratkotrajna akutna upotreba), i u oba slu~aja su klini~ki veoma efikasni. U primarnoj prevenciji se naj~e{}e koriste kao monokomponentni, ali u sekundarnoj ~e{}e kao dvokomponentni preparati (npr. aspirin plus dipiridamol i aspirin plus klopidogrel). Od 11 antitrombocitnih lekova koji se nalaze na tr`i{tu {irom sveta, osam (78%) je dos- tupno u na{oj zemlji. Da bi se postigla savremenost asortimana u na{oj zemlji, postoje}im antitrombocitnim lekovima treba dodati jo{ i parenteralne preparate abciksimaba i tirofibana.

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< The paper was received on 30.06.2014. Accepted on 07.07.2014.

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