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Antiplatelet Therapy
Interactions Between Different P2Y
12
Antagonists
a report by
Natalia Dovlatova and Stan Heptinstall
School of Medical and Surgical Sciences, Division of Cardiovascular Medicine, University of Nottingham Medical School
Currently, attention is focused on the therapeutic use of P2Y
12
receptor different P2Y
12
antagonists work. A direct-acting agent such as cangrelor or
antagonists in patients with cardiovascular pathologies, especially during AZD6140 enters the bloodstream following administration and acts directly
and following coronary interventions. Such drugs inhibit platelet at P2Y
12
receptors on the platelet surface. This prevents any ADP present in
aggregation brought about by adenosine diphosphate (ADP), which plays a the vicinity of the platelet from occupying the receptor and inducing a
central role in platelet function.
1
ADP activates platelets via two specific functional response. The degree of occupation of the receptor by the
receptors on the platelet surface, known as the P2Y
1
and P2Y
12
receptors.
2,3
antagonist depends on the concentration of the drug present in the blood
By blocking the effect of ADP at P2Y
12
receptors, antagonists that act at this plasma, and as this falls (e.g. when infusion of the drug is terminated or no
receptor markedly inhibit platelet aggregation and other aspects of platelet further drug is administered) receptor occupation also falls. As receptor
function and help to prevent thrombus formation.
4
Currently, clopidogrel is occupation falls, the platelets regain their ability to respond to ADP.
the most widely used P2Y
12
antagonist, but this may change as other P2Y
12
antagonists are developed and become available for clinical use. Clopidogrel An indirect-acting agent such as clopidogrel or prasugrel has to be
is a thienopyridine prodrug that needs to be converted into the active converted into an active metabolite before it can act as a P2Y
12
antagonist
metabolite that is responsible for the inhibitory effects of the drug on and reduce platelet function. Following administration of both clopidogrel
platelet function.
5,6
and prasugrel, the active metabolite is generated gradually and reaches
maximum concentration after approximately two hours. Thereafter, the
Prasugrel is a new P2Y
12
antagonist that is also a thienopyridine prodrug concentration of the metabolite decreases quite rapidly, within three hours
and has enhanced potency compared with clopidogrel as a consequence of for clopidogrel and around six hours for prasugrel.
14
Although the
more efficient conversion to its own active metabolite,
7–9
and may prove to metabolite is present in blood only relatively transiently, it interacts
be an important competitor within this class of drugs that inhibit platelet irreversibly with the P2Y
12
receptor, thus producing a long-term effect.
function irreversibly. Once the active metabolites of both clopidogrel and Therefore, unlike the direct-acting, reversible antagonists, the inhibitory
prasugrel are produced they form a covalent disulfide bond between their effects of clopidogrel and prasugrel on platelet function do not disappear
reactive thiol group and a cysteine in the extracellular part of the P2Y
12
once the active metabolite is no longer present in the blood plasma.
receptor, and in this way provide irreversible platelet inhibition.
6,10
There is
also considerable interest in reversible P2Y
12
antagonists, one being So, what happens if different types of drugs are present in the circulation at
cangrelor, which is a potent agent that acts directly at the P2Y
12
receptor the same time? Imagine a situation where cangrelor is still present on P2Y
12
and is being developed as an agent for intravenous use.
11
It differs from receptors at the time that clopidogrel or prasugrel is administered and their
clopidogrel and prasugrel in two important ways. First, the onset of action active metabolites start to be produced. Theoretically, one of two scenarios
of this drug is very rapid: it achieves its maximum inhibitory effect within may arise: the active metabolite may still interact with the receptor replacing
15 minutes after the infusion is initiated, whereas with the prodrugs a the direct-acting antagonist, or the active metabolite may be unable to
certain time is needed for their metabolites to be produced and to be interact with the receptor because the presence of the other antagonist
effective. Second, the drug has a short half-life and completely disappears prevents it from doing so. The first scenario would result in continuation of
within 15 minutes after the termination of infusion,
12
after which platelet inhibition of platelet function when the direct-acting antagonist is no longer
function returns to normal. Another potential drug is AZD6140, which is administered since the active metabolite of clopidogrel or prasugrel will have
also a potent, direct-acting and reversible P2Y
12
antagonist, but with a bound to the P2Y
12
receptor irreversibly and achieved continued inhibition.
longer half-life compared with cangrelor – approximately 12 hours. Unlike However, the second scenario could result in a period during which there is
cangrelor, AZD6140 is being developed for oral administration and has a little or no inhibition of platelet function when the direct-acting antagonist
fairly rapid onset of action, with maximal inhibition of platelet function is no longer administered.
achieved within two to four hours following a single administration.
13
So far, there have been only two studies that have addressed the possible
If and when these various drugs become available, there will be situations influence of cangrelor on the ability of thienopyridine to interact with the
when there is the need to terminate the use of one drug in a certain patient P2Y
12
receptor and inhibit platelet function; there have been no such studies
and replace it with another. The particular situation that comes to mind is using AZD6140. The first was a study by Steinhubl et al. in which cangrelor
following intravenous administration of cangrelor during percutaneous and clopidogrel were administered singly and in combination to healthy
coronary intervention (PCI), when clopidogrel or prasugrel may be volunteers.
15
In this study, administration of cangrelor alone or clopidogrel
prescribed for long-term maintenance antiplatelet therapy. Therefore, the alone provided inhibition of platelet function that was of short and long
question is: will any difficulties be encountered in effecting this transfer from duration, respectively. However, when cangrelor infusion was initiated
one drug to another? To answer this question we need to understand how simultaneously with the administration of clopidogrel and then infusion of
© TOUCH BRIEFINGS 2008 83
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