Antiplatelet drugs pharmacology.pdf

Antiplatelet drugs pharmacology.pdf

• 1.
  ANTIPLATELETS DRUGS Antiplatelet medicationsdivide 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
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  MECHANISM OF ACTION Antiplateletscan 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.
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  Oral thienopyridines selectivelyinhibit 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
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   Upper gastrointestinalbleeding 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.
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  Figure 1: mechanismof action of antiplatelet drug summary
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  Drug Mechanism AdministrationFrequency 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
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  Eptifibatide Integrin alpha 11beta 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