Pharmacology of anti platelet drugs in detail

1. ANTIPLATELETS DRUGS
Antiplatelet medications divide into oral and parenteral agents, and oral
agents subdivide further based on the mechanism of action. Aspirin was the
first antiplatelet medication and is a cyclooxygenase inhibitor. Other oral
antiplatelet includes clopidogrel, ticagrelor, and prasugrel, cilostazol, and
dipyridamole. Glycoprotein IIb/IIIa inhibitors such as tirofiban and
eptifibatide are only available as parenteral agents and are used in acute
phases of acute coronary syndrome. This activity reviews the indications,
contraindications, action, adverse events, and other key elements of
antiplatelet drugs essential to clinical practice
INDICATIONS
Antiplatelet medications divide into oral and parenteral agents. Oral agents
subdivide further based on the mechanism of action. Aspirin was the first
antiplatelet medication and is a cyclooxygenase inhibitor. Other oral
antiplatelet agents include clopidogrel, ticagrelor, prasugrel, pentoxifylline,
cilostazol, and dipyridamole. Glycoprotein IIb/IIIa inhibitors such as
tirofiban and eptifibatide are only available as parenteral agents and are
used in acute coronary syndrome (ACS).
The following is a list of indications of antiplatelet medications:
 Acute coronary syndrome
 Post percutaneous coronary intervention (PCI) with stenting
 Mechanical heart valves in combination with warfarin
 Acute ischemic stroke
 Post percutaneous intervention of peripheral arterial disease
 Device closure of an atrial septal defect (ASD) for at least six months
 Stable angina
 Post-coronary artery bypass grafting surgery
 Essential thrombocytosis
 Primary prevention of coronary artery disease
 Prevention of colon cancer
 Kawasaki disease
 Acute rheumatic disease
 Post patent ductus arteriosus (PDA) device closure for the first six
months
 Acute pericarditis
 Atrial fibrillation with a high risk of stroke
 Primary prevention of venous thromboembolism

2. MECHANISM OF ACTION
Antiplatelets can be classified based on the mechanism of action as follows
1. Cyclooxygenase inhibitors
(Platelet aggregation inhibitors): Aspirin,
Indobufen
2. ADP Receptor antagonist (Oral Thienopyridines):
Ticlopidine
Clopidogrel
Prasugrel
3. ADP Receptor antagonist (Non- Thienopyridines): Cangrelor
Ticagrelor
Elinogrel
4. Glycoprotein IIb/IIIa inhibitors: Abciximab
Tirofiban
Eptifibatide
Defibrotide
5. Phosphodiesterase (PDE3) inhibitors:
Dipyridamole
Cilostazol
Parogrelil
6. Thromboxane A2 receptor inhibitor:
Terutroban
7. Collagen platelet interaction inhibitor:
Monoclonal
antibodies
Aptamers
8. Protease-activated receptor-1 antagonists: Vorapaxar
Aspirin is the most commonly used oral antiplatelet drug. It works by
irreversibly inhibiting the cyclooxygenase enzyme (COX) activity in the
prostaglandin synthesis pathway (PGH2). This prostaglandin is a precursor
of thromboxane A2 (TXA2) and PGI2. Thromboxane A2 works by inducing
platelet aggregation and vasoconstriction, and COX-1 mediates its
production, while PGI2 works by inhibiting platelet aggregation and induces
vasodilation, and is mediated by COX-2. Low-dose aspirin (75 mg to 150 mg)
can induce complete or near-complete inhibition of COX-1, thus inhibiting
the production of TXA2, while larger doses are required to inhibit COX-2.

3. Oral thienopyridines selectively inhibit adenosine diphosphate-induced
(ADP-induced) platelet aggregation. These drugs are converted into the
active drug with the help of the hepatic CYP450 system that can irreversibly
inhibit the platelet P2Y12 receptor. Prasugrel is the most potent of all three
drugs, has a rapid onset of action, and is superior to clopidogrel in patients
undergoing coronary stenting. Ticlopidine has fallen out of favor because of
bone marrow toxicity. Cangrelor is a new intravenous, reversible
P2Y12 receptor antagonist and has a rapid onset of action. It achieves a
significant degree of platelet inhibition compared with clopidogrel.
Glycoprotein platelet inhibitors work by inhibiting glycoprotein IIb/IIIa
(GpIIb-IIIa) receptors on platelets, thus decreasing platelet aggregation, and
most commonly used in ACS. These drugs are only available in an
intravenous form and are therefore used as short-term therapy.
Dipyridamole has antiplatelet and vasodilating properties and
inhibits platelet cyclic nucleotide phosphodiesterase. This enzyme is
responsible for the degradation of adenosine monophosphate (AMP) to
5'AMP, which increases intra-platelet cyclic AMP accumulation and
inhibits platelet aggregation. It also blocks the uptake of adenosine by the
platelets, which also increases cyclic AMP.
Cilostazol is also reported to have vasodilatory, antiplatelet properties, and
antiproliferative effects. It also reduces smooth muscle cell
hyperproliferation and intimal hyperplasia after an injury to the
endothelium
ADMINISTRATION:
Antiplatelet agent administration can be via oral, rectal, or intravenous
routes. Oral medications include aspirin, clopidogrel, ticagrelor, cilostazol,
and dipyridamole. Intravenous drugs include GpII-IIIA inhibitors and can be
used for a short period, most commonly during acute coronary syndromes
before or during PCI. Aspirin is available as a rectal suppository if the
patient cannot take the drug orally.
Individual agent dosing is covered under the articles for each of these drugs
on the Statpearls platform. The reader is advised to seek those articles out
for specific dosing information.
ADVERSE EFFECTS
Following are the most common adverse effects associated with antiplatelet
medications:
 Aspirin-induced asthma
 Nasal polyps

4.  Upper gastrointestinal bleeding because of chronic gastritis
 Ecchymosis
 Haematuria
 Epistaxis
 Ticagrelor-related dyspnea
 Hemorrhage
 Thrombocytopenia
Headache, nausea, diarrhea, pain, infection, upper respiratory symptoms,
palpitations, arrhythmias, and peripheral edema are the most common side
effects associated with cilostazol
CONTRAINDICATIONS:
The most common contraindications for using antiplatelet agents are as
follows
 Large esophageal varices
 Recent stroke within two years
 History of intracranial Hemorrhage
 Significant thrombocytopenia
 Major surgery with 72 hours
 Hypersensitivity to the medication
 Acute clinically significant bleed
 End-stage renal disease on haemodialysis
 Decompensated liver cirrhosis
 Severe hypertension with a BP over 200/110 mmHg
 Congestive heart failure is a contraindication for the use of cilostazol
TOXICITY
Aspirin is the most commonly used of all antiplatelet drugs, so accidental
intake is common. The effect can be life-threatening if taken over 150 mg/kg
of body weight. Supportive measure to decrease the absorption of the drug is
achievable by using activated charcoal but only if administered within 4
hours of ingestion. The patient will need monitoring for signs and symptoms
of bleeding and the development of metabolic derangements, such as
acidosis. If acidosis develops, immediate dialysis is indicated.
There is no antidote available for most of these drugs; however, a
monoclonal antibody against ticagrelor is in development, but it is not
commercially available as yet.

5. Figure 1: mechanism of action of antiplatelet drug summary

6. Drug Mechanism Administration Frequency Side effects Limitations
Aspirin
Irreversible acetylation of
Ser529 of cyclooxygenase 1
Oral Daily
Bleeding,
GIT Toxicity
 Heartburn,
indigestion,
 Nausea,
 Vomiting and
ulceration
Weak antiplatelet drugs
Ticlopidine
The active metabolite
irreversibly inhibit P2Y12
receptors
Oral Twice daily
Bleeding,
GIT Toxicity,
 Heartburn,
 Indigestion,
 Nausea,
 Vomiting
 Ulceration.
Rashes.
Neutropenia.
Thrombotic
Thrombocytopenic
Purpura
More side effects than
clopidogrel.
Clopidogrel
The active metabolite
irreversibly inhibit P2Y12
receptors
Oral Daily
Bleeding,
Rash,
Neutropenia,
Thrombocytopenic
Purpura
Patient to patient variability in
response
Prasugrel
The active metabolite
irreversibly inhibit P2Y12
receptors
Oral Daily Bleeding
More haemorrhagic side effects,
greater cost than clopidogrel,
contraindicated in stroke and MI
Patients, not recommended in
patient above 75 years of age at
high risk of CVS problems
Abciximab
Integrin alpha 11 beta 3
antagonist
Intravenous Once
Bleeding
Thrombocytopenia
EDTA induced pseudo
thrombocytopenia
Requires intravenous injection

7. Eptifibatide
Integrin alpha 11 beta 3
antagonist
Intravenous Once
Bleeding
Thrombocytopenia
EDTA induced pseudo
thrombocytopenia
Requires intravenous injection
Tirofiban
Integrin alpha 11 beta 3
antagonist
Intravenous Once
Bleeding
Thrombocytopenia
EDTA induced pseudo
thrombocytopenia
Requires intravenous injection
Dipyramidole
Antiplatelet and vasodilatory
effects through inhibition of
cyclic nucleotide
phosphodiesterase and of
adenosine uptake
Oral
Two or three
times daily
Headache,
Dizziness,
Hypotension,
Blood pressure liability,
flushing,
GIT Toxicity:
 Nausea,
 Vomiting,
 Diarrhoea
 Pain.
Rash.
The benefit is more evident in
combination with aspirin low
dose
Cilostazol
Antiplatelet and vasodilatory
effects through inhibition of
cyclic nucleotide
phosphodiesterase 3
Oral Twice daily
Bleeding,
Headache,
Diarrhoea,
Palpitations,
Dizziness,
Rash,
Pancytopenia
Side effects leads to
discontinuation of drug in
almost 15% patients