GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

Available online at GSC Online Press Directory

GSC Biological and Pharmaceutical Sciences

e-ISSN: 2581-3250, CODEN (USA): GBPSC2
Journal homepage: https://www.gsconlinepress.com/journals/gscbps

(R E V I E W A R T I C L E )

Antiplatelet drugs overview

Latif Sarah Younis *, Issa Mustafa Mohammed, Hassan Tabark Najah and Ali Murtadha Haider

College of Pharmacy, Al-Nahrain University, Iraq.

Publication history: Received on 07 January 2020; revised on 15 January 2020; accepted on 19 January 2020

Article DOI: https://doi.org/10.30574/gscbps.2020.10.1.0003

Abstract
Platelets are essential factor in the pathophysiology of atherothrombosis, abnormal platelet function guiding to many
cardiovascular complications such as myocardial infarction and ischemic stroke. There are numerous antiplatelet drugs
approved for use in the clinical management and several under examination. Antiplatelet drugs with the high potency
are mostly associated with the intensifying incidence of bleeding. Aspirin and clopidogrel (alone or dual) are the mostly
used drugs with the best favorable risk-benefit profiles of drugs available. While cangrelor and ticagrelor may produce
further benefits but need more studies .Other drugs such as prasugrel, dipyridamole and cilostazol are not widely used.

Keywords: Aspirin; Thienopyridines; Coronary heart disease

1. Introduction
Platelets are vital parts of normal hemostasis and key components in atherothrombosis .Therefore, the diseases that
associated with thrombus formation such as arteriosclerosis are treated mainly by antiplatelets drugs [1].

Platelets are non-nucleated cells that formed from megakaryocyte and have a maximum circulating life span of 7-10
days. Adjustment of platelet production is mediated by thrombopoietin, which is produced by liver, bone marrow and
kidney, binding to high-affinity receptors on platelets and megakaryocytes [2].

Platelets provide a circulating source of chemokines, cytokines, and growth factors, which are preformed and packaged
in storage granules. Although platelet adhesion, activation, and aggregation regarded as a normal repairing response to
the sudden fissuring or rupture of an atherosclerotic plaque, but uncontrolled progression of such process can cause
intraluminal thrombus formation, vascular occlusion, and subsequent ischemia or infarction [3].

As noted in figure 1, Thrombin binds to protease activated receptor1(PAR-1), which leads to shape change,
phospholipase C (PLC) activation, thromboxane A2 (TXA2) generation, and activation of the glycoprotein (GP) IIb/IIIa
receptor, resulting in sustained platelet aggregation. Cyclooxygenase (COX)-1 catalyzes the production of TXA2, a
potent platelet aggregator, generated by platelets activated by thrombin and other agonists [4].

Adenosine 5′-diphosphate (ADP) binds to its 7-transmembrane domain receptors, P2Y1 and P2Y12, to activate platelets.
P2Y1 is coupled to Gαq and G12. Gαq is linked to a signaling pathway involving PLC activation, resulting in a rise in the
intracellular calcium concentration ion [Ca+2] and protein kinase C (PKC) activation, leading to GP IIb/IIIa activation
and transient platelet aggregation [4].


Corresponding author
E-mail address:
Copyright © 2020 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0.
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

G12 mediates platelet shape change. P2Y12 is linked to Gαi-coupled signaling cascades associated with adenylcyclase
(Ac) down-regulation and decreased cyclic-3′, 5′-monophosphate (cAMP) production, which mediates GP IIb/IIIa
receptor activation, leading to sustained platelet aggregation [4].

Although activated platelets are incapable of de novo protein synthesis, they can translate constitutive mRNA into
protein over the course of several hours. Thus, platelets may play a role in inflammation, angiogenesis, and wound
healing, and antiplatelet therapies may have an impact on these processes by blocking platelet-derived protein signals
for inflammatory or proliferative responses [5].

In addition to cardiac troponin I, Myeloperoxidase is another test used for the inspection of the existence of
inflammatory reaction and oxidation that escorted thrombus formation and aggravated acute atherosclerosis
symptoms [6].

Antiplatelet drugs are indicated for the management of thrombotic diseases that included stroke, acute myocardial
infarction (AMI), acute coronary syndrome (ACS), angina, percutaneous coronary intervention (PCI), cardiac surgery,
primary and secondary cardiovascular disease prevention, peripheral vascular disease, and thrombotic disorders such
as atrial fibrillation.

Figure 1 Platelet activation pathways and antiplatelet drugs targeting [4]

2. Classes of antiplatelet drugs

2.1. Platelet cyclooxygenase (COX-1) inhibitor

2.1.1. Aspirin
Aspirin is the backbone treatment for all state of atherothrombosis. The effectiveness of aspirin on platelet came from
its ability to irreversibly inhibit platelet cyclooxygenase (COX-1), by acetylating a serine located near the active site of
the enzyme, that is responsible for the conversion of arachidonic acid to prostaglandin (PGH2) and thereafter
production of thromboxane A2 (TxA2) and prostocycline (PGI 2) [3].

Human platelets and vascular endothelial cells form PGH 2 to produce primarily TXA 2 and PGI 2, respectively. TXA 2
induces platelet aggregation and vasoconstriction, whereas PGI 2 inhibits platelet aggregation and induces vasodilation
.Fulfilled inhibition of platelet COX-1 and then TXA 2 can occur with low daily doses of aspirin (75-150 mg). Conversely,
the endothelium COX-2 generates PGI2 and is less sensitive to aspirin inhibition. As a result, low-dose aspirin has limited
effects on PGI2-dependent vascular functions including arterial blood pressure regulation [7].

Aspirin is rapidly absorbed after oral administration in the stomach and upper intestine.it is achieved plasma peak levels
on 30 - 40 min. and it is inhibit platelet function within 1 hr. while enteric-coated aspirin form take more time to reach
plasma peak levels. The lower bioavailability of some enteric-coated preparations and their poor absorption from small
intestine may result in inadequate platelet inhibition when these preparations are used at low doses [8].

82
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

Aspirin irreversibly inactivates platelet COX-1, therefore in spite of the rapid clearance of aspirin from the circulation,
the platelet-inhibitory effects last for the life span of the platelet (10 days).Additionally, aspirin acetylates
megakaryocyte COX-1, thereby inhibiting thromboxane production in newly released platelets [9].

The major adverse effect of aspirin intake is enhanced risk of bleeding tendency especially by gastrointestinal tract
although this risk may be amended by the use of gastro protective drugs such as proton pump inhibitors (PPIs) [10].
The concomitant intake of nonselective reversible COX-1 inhibitors such as ibuprofen or naproxen with aspirin can
interfere with the antiplatelet effect of low-dose aspirin and performing aspirin less effective when used for
cardioprotection or stroke prevention. Interestingly, a competition exist between the nonselective COX inhibitors and
aspirin for the common binding site within the COX-1 channel ,which may prevent aspirin from acetylating the serine
residue and lead to aspirin resistance [11].

The incapability of aspirin to inhibit COX-1–dependent TXA2 production is called aspirin resistance, and it is about 1–
2%. High On-Treatment Platelet Reactivity (HPP) or resistance to antithrombotic drug is consider as an adverse
thrombotic events or treatment failure which is associated with increase the risk of MI, stroke, or death [12].

Many factors effect on the platelet reactivity such as age, female sex, diabetes, concomitant therapies (particularly
NSAIDs, e.g, ibuprofen). Conditions that associated with an inflammatory response such as unstable angina, acute
myocardial infarction (AMI), diabetes, and cardiac surgery are associated with HPR in aspirin-treated patients [13].

2.2. Platelet P2Y12 -ADP receptor irreversible inhibitor (Thienopyridines)

Thienopyridines class involved three generations, ticlopidine, clopidogrel, and prasugrel. All of them are prodrugs that
must converted by metabolic activation through the hepatic CYP450 system to their active metabolites that selectively
inhibit the platelet P2Y12 -ADP receptor [14].

2.2.1. Ticlopidine
The first generation thienopyridines,Ticlopidine, has limited use due to its bone marrow toxicity, neutropenia, aplastic
anemia, and thrombotic thrombocytopenic purpura [15].

2.2.2. Clopidogrel
Clopidogrel, a second generation thienopyridine, is a prodrug that irreversibly binds to the P 2 Y 12-ADP platelet
receptor by forming disulfide bridges after a two-stage of activation by cytochrome P450 (CYP) liver isoenzymes.
Conspicuously, clopidogrel is more safer than ticlopidine, and is more effective than aspirin for prevention of secondary
vascular events .As clopidogrel and aspirin act on discrete and complementary pathways of platelet inhibition, dual
therapy is evaluated in high-risk clinical conditions [16].The use of clopidogrel is certified for the reduction of
atherosclerotic events in diabetic patients and in patients with recent stroke, recent MI,or established peripheral
arterial disease [17,18].

After oral administration of clopidogrel, the drug is variable absorbed. 108 and the majority of absorbed clopidogrel
(85%) is extensively hydrolyzed by esterases to the inactive carboxylic acid metabolite. In the liver, clopidogrel is
metabolized in a 2-step process by CYP3A4/3A5 and CYP2B6 / 1A2/2C9/2C19 to a very short-lived active metabolite ,
which is responsible for its effect on platelet aggregation [19].

Peak concentrations of the parent drug, its active metabolite and the carboxylic acid metabolite occur within 1- 2 hr
.The drug and its metabolite are extensively bound to serum proteins. Elimination is by the feces (50%) and urine (50%).
Inhibition of platelet aggregation reaches a steady state 50 - 60% inhibition after 4 - 7 days of daily administration of
75 mg [20].

There are interpatient variability’s in response to clopidogrel and thereafter in antiplatelet activity ,the most important
one is the genotype variability of liver cytochrome enzyme e.g.CYP2C19 genotypes are associated with diminished
platelet response to clopidogrel but this may be overcome by monitoring and adjusting the dose based on the platelet
reactivity [21].

Loading dose of 300 mg of clopidogrel results in more-rapid platelet inhibition than is achieved with the 75 mg
maintenance dose. Moreover, inhibition of ADP-induced platelet aggregation was also significantly greater with a 600-
mg loading dose of clopidogrel compared with a 300-mg loading dose [22].

83
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

The major side effect of clopidogrel administration is the increased risk of bleeding. Compared with aspirin, there were
fewer GI symptoms but an increased incidence of diarrhea and rash. A rare but significant complication of clopidogrel
is the development of thrombotic thrombocytopenic purpura [23].

Because of the requirement for metabolism of clopidogrel by CYP3A4/3A5 to generate the active metabolite, many
drugs that metabolize by CYP3A or CYP2C19, e.g. statins drug or proton pumps inhibitors drugs respectively can
interfere with the metabolism of clopidogrel and thereafter with its clinical effect. Concurrent used of atorvastatin with
clopidogrel may provoke hepatic injury cholestasis type resulting from abnormal bile flow caused by either drugs or
their metabolites [24]. Additionally, atorvastatin has been found to amend the functions of endothelium by its effect on
peroxisome –proliferator-activated receptors (PPAR-α) pathway [25].

Erythromycin, calcium antagonists, macrolide antibiotics, or ketoconazole,CYP3A inhibitors, can produce lessening in
antiplatelet activity of clopidogrel .While Rifampin, a CYP3A inducer, can reveal enhancing antiplatelet activity of
clopidogrel [26].

Many studies found that there are variability in patient’s response to clopidogrel and may be associated with adverse
thrombotic events especially in those with high on-treatment platelet reactivity. Particularly, Several factors can
associate with increased incidence of high platelet reactivity in patients with clopidogrel such as diabetes, dyslipidemia,
concomitant therapies that effect on metabolism of clopidogrel and related to insufficiency of active metabolite such as
(lipophilic statins, e.g, simvastatin and atorvastatin; proton pump inhibitors, eg, omeprazole; and calcium channel
blockers), and genetic polymorphisms of CYP450 isoenzymes (2C19, 1A2, 2B6, 2C9, 3A4) that involved in the
production of clopidogrels' active metabolite [27].

2.2.3. Prasugrel
Prasugrel, a prodrug of the thienopyridine family, after a rapid one-step conversion by CYP3A4 and to a lesser extent
CYP2B6 into a highly bioavailable metabolite, causes an irreversible block of the P2Y12 ADP receptor prevent platelet
activation. Because of a distinct chemical structure, the conversion to its active metabolite is less dependent on specific
cytochrome P450 enzymes than that of other thienopyridines [28].

In patients with stable coronary artery disease, prasugrel produced a faster and more effective inhibition of platelet
function than clopidogrel. The incidence of poor platelet aggregation response after prasugrel 60 mg administration
was lower than for clopidogrel 300 mg [29].

Prasugrel is rapidly absorbed after oral ingestion, unaffected by food, and is rapidly converted to its active metabolite,
which reaches peak concentrations within 30 min of dosing. The active metabolite has a half-life of 4 h, and renal
excretion is the major route for elimination of the metabolites. Prasugrel is gave as 60 mg loading and 10 mg
maintenance doses [30].

The major adverse effect of prasugrel is bleeding. Prasugrel is a more potent inhibitor of platelet function than
clopidogrel and therefore it associated with a significantly increased incidence of major adverse bleeding events and
should be avoided in patients with known cerebrovascular disease [31]. There were a little probability of interactions
with other drugs metabolized by cytochrome P450 system (CYP3A4/CYP2B6) as reported in many studies [32].

Compared with clopidogrel, use of prasugrel cause few nonresponders and better clinical response in diabetic patients.
Poor response to clopidogrel was attributed to reductions in the amount of measured active metabolite available to
interact with platelets as opposed to alterations in the platelet P2Y12 receptor [33].

2.3. ADP- receptor antagonists

2.3.1. Cangrelor
Cangrelor, an adenosine triphosphate (ATP) analog, is a reversible inhibitor of the platelet P2Y12- ADP receptor. It
achieves greater inhibition of platelet aggregation than that obtained by clopidogrel. But other study found that the
measurement of inhibition of platelet aggregation did not exhibit any variation between cangrelor and clopidogrel [34,
35].

Cangrelor present as IV-form, has a rapid onset of action (steady state at 30 min.) and elimination half-time of 9 min.
Moreover, platelet activity rapidly return to its normal state within 60 minutes after interruption of drug. Cangrelor

84
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

metabolized by sequential dephosphorylation in plasma therefore it can be used in patients with renal or hepatic
function abnormalities [36].

The most common adverse effects of cangrelor treatment include, bleeding, transient increases in liver enzymes, and
dyspnea [37]. Cangrelor can interact with the platelet inhibitory activity of clopidogrel at active site on platelet when
given concurrently. Therefore, clopidogrel can be gave consecutively after cangrelor. Hence, cangrelor might consider
as P2Y12 inhibitor bridge therapy in the perioperative and operative period [38].

2.4. Platelet P2Y12 -ADP receptor reversible inhibitor

2.4.1. Ticagrelor
Ticagrelor, an orally active cyclopentyl-triazolopyrimidine, binds to the P 2 Y 12 receptor, other than those recognized
by ADP, in a reversible manner and almost completely inhibits ADP-induced platelet aggregation. It has a faster onset
and offset of platelet inhibition than clopidogrel [39].

After oral administration, ticagrelor is rapidly absorbed and does not require hepatic biotransformation to be
pharmacologically active. It is peak effect on platelet inhibition was 2 - 4 hours. The terminal half-life was approximately
7 hours. of addition, ticagrelor is also metabolized to an equipotent, active metabolite by CYP 3 A 4 enzymes thereafter
both ticagrelor and its active metabolite excreted by the intestinal route, no dose adjustment is required in kidney
failure. ticagrelor is given in a loading dose of 180 – 270 mg daily and in a maintanence dose of 90-mg twice daily to
optimize its efficacy, safety, and tolerability [40].

The most common adverse event with ticagrelor intake is bleeding .Major, life-threatening, or fatal bleedings did not
differ between those on ticagrelor and those on clopidogrel. Another adverse events is dyspnea which is reversible and
required cessation of therapy when begin [41].

A reversible increase in serum uric acid and creatinine also noted. Additionally, nausea, hypotension, and asymptomatic
ventricular pauses may occur because of an adenosine-mediated response. Therefore, ticagrelor treatment was
precautioned in patients with hyperuricemia, bradyarrhythmias without pacemakers, and syncope (fainting) and in
those at high risk of bleeding (e.g. elderly, low bodyweight, renal dysfunction) and avoided in patients with history of
stroke [42].

2.5. Phosphodiesterase inhibitor drugs

2.5.1. Dipyridamole
Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. It is act by inhibition of
nucleotide phosphodiesterase, an enzyme that destroys cyclic adenosine monophosphate (cAMP), causing increase in
intraplatelet cyclic AMP which resulted in inhibition of platelet aggregation and blockade of adenosine uptake thereby
increasing the amount of adenosine at the platelet vascular interface. In addition, dipyridamole directly stimulate the
synthesis and release of prostacyclin (PGI2) from the endothelium [43].

After oral administration, dipyridamole is variably absorbed from gastrointestinal tract that lead to variable levels of
its systemic bioavailability. Recently this feature has been amended with the addition of low-concentration of aspirin to
dipyridamole and form a sustained release drug. Dipyridamole is greatly bound to albumin, exposed to enterohepatic
recirculation, after conjugated to glucuronide it’s mainly excreted by bile [44].

Use of dipyridamole is associated with an increased risk of bleeding events. The most common adverse effect of chronic
administration is headache. In high doses, dipyridamole -induced vasodilation and tachycardia may produce myocardial
ischemia, which may be a limiting factor for its use as an antiplatelet drug [45].

The dual therapy of dipyridamole and aspirin caused increase the risk of headache and bleeding. Moreover, As
dipyridamole has vasodilator properties therefore additive vasodilation and hypotensive effects may occur when taken
with other vasodilator drugs such as angiotensine converting enzyme (ACE) inhibitors inhibitors [46].

2.5.2. Cilostazol
Cilostazol, 2-oxoquinolone derivative, selectively inhibit intracellular phosphodiesterase type 3 enzyme that sequently
lead to inhibit platelet aggregation and vasodilation. Cilostazol intake in a dose of 50 mg bid or 100 mg once daily was
found to increase maximal and pain-free walking distance in patients with intermittent claudication [47], and averts

85
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

stent thrombosis and restenosis [48]. In diabetic patients on standard dual antiplatelet therapy (aspirin and
clopidogrel), adjunctive treatment with cilostazol enhances inhibition of platelet P 2 Y 12 signaling [49].

Orally intake cilostazol has variable level of absorption. It is abundantly bound to albumin and metabolized primarily
by CYP3A4/5 to inactive metabolites that eliminated by urine.The elimination half-time for cilostazol is approximately
10 hours [50].

Cilostazol treatment especially at the first –two weeks caused gastrointestinal side effects, and headache that was the
basis of drug interruption by some patients. Similarly to dipyridamole, Cilostazol caused hypotension and tachycardia
as a result of vasodilation. Therefore,it is contraindicated in patients with heart failure [51].

As cilostazol metabolized by CYP3A4 and CYP2C19 therefore, it may interfere with other drugs metabolized by these
enzymes such as omeprazole (CYP2C19 inhibitor) or erythromycin (CYP3A4 inhibitor) that may lead to deteriorate its
biological level [52].

2.6. GpIIb-IIIa receptor antagonists

This class of drugs involve Abciximab (monoclonal antibody) and Tirofiban (non-peptide tyrosine derivative) both are
intake as IV bolus dose and are selectively bounds to GpIIb-IIIa receptor of platelet and inhibit its binding to fibrinogen
and aggregation [53].

2.6.1. Abciximab
Abciximab is a monoclonal antibody inhibits not only GP IIb-IIIa receptor but also GP Ib receptor for von Willebrand
factor (vWF) on platelets, thereby decreasing aggregation through fibrinogen and adhesion through vWF [54].

After IV bolus administration (0.25 mg/kg), abciximab rapidly bound to GpIIb-IIIa and 80% of the GpIIb-IIIa receptors
blocked and platelet aggregation diminished to 20% of baseline. Half-life of equal to about 30 min. After 2hr. the clinical
effect of abciximab was observed and after 24hr. the platelet activity and bleeding time regularly restore to normal [55].

It is used to decrease ischemic events of managed acute coronary syndrome and as adjunctive therapy during
percutaneous coronary intervention (PCI), but trials with orally administered GP IIb-IIIa inhibitors have failed to
demonstrate any benefit [56]. Thrombocytopenia is the main adverse effect that showed in 1- 2% of the treated patients
and with re intake of the drug the incidence of thrombocytopenia elevated [55].

3. Conclusion
Antiplatelet drugs are used to avoid the formation of platelet-rich arterial thrombi, while anticoagulants drugs are used
to avert the formation of fibrin-rich thrombi such as left atrial appendage thrombi. The appearance of many adverse
effects of Antiplatelet drugs such as bleeding, and inter individual response variability enhanced the requirement for
laboratory and genetic information to pursue the therapeutic monitoring for each patients.

Compliance with ethical standards

Acknowledgments
The authors would like to impart their sincere thanks to the Dean of Pharmacy College, Al-Nahrain University in Iraq,
for the strengthening to execute this Article.

Disclosure of conflict of interest

No conflicts of interests to assert.

References
[1] Bhatt DL. (2009). Role of antiplatelet therapy across the spectrum of patients with coronary artery disease.
American journal of cardiology, 103, 11A–9A.

86
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

[2] Kaushansky K. (2009).Determinants of platelet number and regulation of thrombopoiesis. Hematology-

American Society of Hematology Education Program, (1), 147 - 152.
[3] Davì G and Patrono C. (2007). Platelet activation and atherothrombosis. New England Journal of Medicine,
357(24), 2482 - 2494.
[4] Di Minno MND, Guida A, Camera M, Colli S , Di Minno G, and Tremoli E. (2011).Overcoming limitations of current
antiplatelet drugs: A concerted effort for more profitable strategies of intervention. Annals of Medicine, 43, 531–
544.
[5] Lindemann S, Tolley ND, Dixon DA, McIntyre TM, Prescott SM, Zimmerman GA, et al . (2001).Activated platelets
mediate infl ammatory signaling by regulated interleukin 1-beta synthesis.Journal of Cell Biology, 154(3), 485 -
490.
[6] Rada FH. (2018). Oxidative stress and some inflammatory biomarkers in patients with coronary heart disease.
European journal of pharmaceutical and medical research, 5(1), 9 -12.
[7] Patrono C, Baigent C, Hirsh J and Roth G. (2008). Antiplatelet drugs: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (8th Edition). Chest,133, 199S–233S
[8] Cox D, Maree AO, Dooley M, Conroy R, Byrne MF and Fitzgerald DJ. (2006). Effect of enteric coating on antiplatelet
activity of low-dose aspirin in healthy volunteers. Stroke, 37(8), 2153 - 2158.
[9] Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F, et al . (1985). Clinical pharmacology of
platelet cyclooxygenase inhibition. Circulation, 72(6), 1177 - 1184.
[10] Lai KC, Lam SK, Chu KM, Wong BC, Hui WM, Hu WH, et al. (2002). Lansoprazole for the prevention of recurrences
of ulcer complications from long-term low-dose aspirin use. New England Journal of Medicine, 346, 2033–8.
[11] US Food and Drug Administration. (2010). Information for Healthcare Professionals: Concomitant Use of
Ibuprofen and Aspirin. Rockville, MD: FDA Medwatch.
[12] Cattaneo M. (2007). Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. Journal of
Thrombosis and Haemostasis, 5, 230–7.
[13] DiChiara J, Bliden KP, Tantry US, Hamed MS, Antonino MJ, Suarez TA, et al. (2007). The effect of aspirin dosing on
platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect
(ASPECT) study. Diabetes, 56, 3014–9.
[14] Savi P and Herbert JM. (2005).Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists
for the prevention of atherothrombosis. Seminars in Thrombosis and Hemostasis, 31(2), 174 - 183.
[15] Urban P, Macaya C, Rupprecht HJ, Kiemeneij F, Emanuelsson H, Fontanelli A, et al. (1998). Randomized evaluation
of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the
multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation, 98, 2126 – 32.
[16] CAPRIE Steering Committee. (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk
of ischaemic events (CAPRIE). Lancet, 348, 1329–39.
[17] Rada FH. (2016). Clopidogrel and liver injury in diabetic patients. European journal of pharmaceutical and
medical research, 3(6), 168-170.
[18] Hasan NA, Al Baghdadi MH and Rada FH. (2014). Assessment of adverse effect of atorvastatin with platelet
P2Y12-ADP receptor antagonist on platelets aggregation and renal function in coronary heart disease treated
patients. International journal of research in pharmacy and chemistry, 4(2), 274-282.
[19] Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS II, Brandt JT, et al. (2007). Cytochrome P450 3A inhibition
by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clinical
Pharmacology and Therapeutics, 81, 735–41.
[20] Hochholzer W, Trenk D, Frundi D, Blanke P, Fischer B, Andris K, et al. (2005).Time dependence of platelet
inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous
coronary intervention. Circulation, 111, 2560–4.
[21] Shuldiner AR,O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. (2009). Association of cytochrome
P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. Journal of the
American Medical Association, 302, 849–57.

87
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

[22] Cuisset T , Frere C , Quilici J , Morange PE, Nait-Saidi L ,Carvajal J, et al .(2006). Benefit of a 600-mg loading dose
of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute
coronary syndrome undergoing coronary stenting .Journal of American College of Cardiology , 48 (7),1339 - 1345
.
[23] Serebruany VL, Malinin AI, Ferguson JJ, Vahabi J, Atar D and Hennekens CH. (2008). Bleeding risks of combination
vs. single antiplatelet therapy: a meta-analysis of 18 randomized trials comprising 129,314 patients.
Fundamental and Clinical Pharmacology, 22, 315–21.
[24] Rada FH, Hasan NA and Al Baghdadi MH. (2015). Hepatotoxicity of Combined Therapy of Atorvastatin with
Platelet P2Y12-ADP Receptor Antagonist in Coronary Heart Disease Treated Patients. The Iraqi Postgraduate
Medical Journal, 14(1), 108 -113.
[25] Rada FH. (2019).Peroxisome Proliferator- Activated Receptors Family Overview. European Journal of
Pharmaceutical and Medical Research, 6(1), 167-170.
[26] Siller-Matula JM, Lang I, Christ G and Bernd Jilma B. (2008).Calcium-channel blockers reduce the antiplatelet
effect of clopidogrel. Journal of the American College of, 52, 1557-1563.
[27] Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ and Becker R. (2010).Working Group on High On-
Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet
reactivity to adenosine diphosphate. Journal of American College of Cardiology, 56 (12), 919 - 933.
[28] Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, et al. (2006). Interactions of two major
metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metabolism and
Disposition, 34, 600–7.
[29] Braun OO, Johnell M, Varenhorst C, James S, Brandt JT, Jakubowski JA, et al.(2008). Greater reduction of platelet
activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary
artery disease.Thrombosis and Haemostasis, 100, 626–33.
[30] Farid NA, Smith RL, Gillespie TA, Rash TJ, Blair PE and Kurihara A. (2007). The disposition of prasugrel, a novel
thienopyridine, in humans. Drug Metabolism and Dispositions, 35 (7), 1096-8.
[31] Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. (2007). Prasugrel versus
clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 357, 2001–15.
[32] Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, et al. (2008).Effects of the proton pump inhibitor
lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Journal of Clinical
Pharmacology, 48, 475–84.
[33] Erlinge D, Varenhorst C, Braun OO, James S, Winters KJ, Jakubowski JA, et al. (2008).Patients with poor
responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite,
but their platelets respond normally to active metabolite added ex vivo. Journal of American College of
Cardiology, 52, 1968–77.
[34] Storey RF, Wilcox RG and Heptinstall S. (2002). Comparison of the pharmacodynamic effects of the platelet ADP
receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets, 13, 407–
13.
[35] Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM, et al. (2009). Platelet inhibition with
cangrelor in patients undergoing PCI.New England Journal of Medicine, 361, 2318–29.
[36] Fugate SE and Cudd LA. (2006).Cangrelor for treatment of coronary thrombosis. Annals of Pharmacotherapy, 40,
925–30.
[37] Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G,et al. (2009). Intravenous platelet blockade
with cangrelor during PCI. New England Journal of Medicine, 361, 2330 – 41.
[38] Steinhubl SR, OH JJ, Oestreich JH, Ferraris S, Charnigo R and Akers WS. (2008).Transitioning patients from
cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thrombosis Research, 121, 527–34.
[39] Rada FH. (2018).Antiplatelet Adequacy of Cytopentyl Triazolopyrimidine versus Clopidogrel in Patients with
Coronary Heart Disease. Asian Journal of Pharmaceutical and Clinical Research, 11(12), 536 -539.
[40] Teng R and Butler K. (2010). Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending
doses of ticagrelor, a reversibly binding oral P 2Y(12) receptor antagonist,in healthy subjects. European Journal
of Clinical Pharmacology, 66, 487–96.

88
 Latif et al. / GSC Biological and Pharmaceutical Sciences, 2020, 10(01), 081–089

[41] Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. (2009). Ticagrelor versus clopidogrel
in patients with acute coronary syndromes. New England Journal of Medicine, 361, 1045–57.
[42] Bhatt DL. (2007).Intensifying platelet inhibition-navigating between Scylla and Charybdis. New England Journal
of Medicine, 357, 2078 – 81.
[43] Born G and Patrono C. (2006). Antiplatelet drugs. British Journal of Pharmacology, 147 (1) , S241 - S251 .
[44] Müller TH, Su CA, Weisenberger H, Brickl R, Nehmiz G and Eisert WG. (1990). Dipyridamole alone or combined
with low-dose acetylsalicylic acid inhibits platelet aggregation in human whole blood ex vivo. British Journal of
Clinical Pharmacology, 30(2), 179 - 186.
[45] Weinberger J. (2005).Adverse effects and drug interactions of antithrombotic agents used in prevention of
ischaemic stroke. Drugs, 65, 461–71.
[46] Serebruany VL, Malinin AI, Eisert RM and Sane DC. (2004). Risk of bleeding complications with antiplatelet
agents: metaanalysis of 338,191 patients enrolled in 50 randomized controlled trials. American Journal of
Hematology, 75, 40–7.
[47] Thompson PD, Zimet R, Forbes WP and Zhang P. (2002). Meta-analysis of results from eight randomized, placebo-
controlled trials on the effect of cilostazol on patients with intermittent claudication. American Journal of
Cardiology, 90 (12), 1314 - 5.
[48] Biondi-Zoccai GG ,Lotrionte M , Anselmino M , Moretti C, Agostoni P, Testa L,et al.(2008). Systematic review and
meta-analysis of randomized clinical trials appraising the impact of cilostazol after percutaneous coronary
intervention. American Heart Journal, 155 (6), 1081 - 8.
[49] Angiolillo DJ, Capranzano P, Goto S, Aslam M, Desai B, Charlton RK, et al.(2008). A randomized study assessing
the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease
on dual antiplatelet therapy: results of the OPTIMUS-2 study.European Heart Journal, 29, 2202 – 11.
[50] Hiratsuka M, Hinai Y, Sasaki T, Konno Y, Imagawa K, Ishikawa M, et al. (2007).Characterization of human
cytochrome p450 enzymes involved in the metabolism of cilostazol. Drug Metabolism and Disposition, 35, 1730–
2.
[51] Gamssari F, Mahmood H, Ho JS, Villareal RP, Liu B, Rasekh A, et al.(2002). Rapid ventricular tachycardias
associated with cilostazol use. Texas Heart Institute Journal, 29, 140–2.
[52] Suri A, Forbes WP, Bramer SL. (1999). Effects of CYP3A inhibition on the metabolism of cilostazol. Clinical
Pharmacokinetics, 37, 61–8.
[53] Kereiakes DJ, Kleiman NS, Ambrose J, Cohen M, Rodriguez S, Palabrica T, et al.(1996). Randomized,double-blind,
placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients
undergoing coronary angioplasty.Journal of American College of Cardiology,27 (3), 536 - 542 .
[54] Sharma HL and Sharma KK. (2007). Principles of pharmacology. 1st ed. Hyderabad: Paras medical publishers;
Drugs affecting coagulation, fibrinolysis and platelet functions, 639, 703,704.
[55] Tcheng JE, Kereiakes DJ , Lincoff AM , George BS, Kleiman N, Sane DC, et al .(2001). Abciximab readministration:
results of the ReoPro Readministration Registry. Circulation, 104 (8), 870 - 875.
[56] Gross PL and Weitz JI. (2009).New antithrombotic drugs. Clinical Pharmacology and Therapeutics, 86, 139-46.

How to cite this article

Latif SY, Issa MM, Hassan TN and Ali MH. (2020). Antiplatelet drugs overview. GSC Biological and Pharmaceutical
Sciences, 10(1), 81-89.

89