Mechanism of Action
clopidogrel is an inhibitor of platelet aggregation.A variety of drug that inhibit platelet function have been shown to decrease morbid events in people with establish atherosclerotic cardiovascular disease as evidenced by strock or transient ischemic attacks.myocardial infarction or need for bypass or angioplasty.This indicates that platelets particiption in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.
Pharmacodynamics
Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Plavix. Repeated doses of 75 mg Plavix per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Plavix per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
Metabolism
Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450
enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively.
Pharmacokinetics
Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
Elimination
Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.
Indication for used
Clopidogrel is used to prevent strokes and heart attacks in patients at risk for these problems. Clopidogrel is in a class of medications called antiplatelet drugs. It works by helping to prevent harmful blood clots that may cause heart attacks or strokes.
Side effects
Clopidogrel may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
Clopidogrel Dosing Information
Usual Adult Dose for Ischemic Stroke:
75 mg orally once a day with or without food.
Aspirin therapy should be initiated and continued in combination with clopidogrel.
Adult Dose for Myocardial Infarction:
75 mg orally once a day with or without food.
Aspirin therapy should be initiated and continued in combination with clopidogrel.
Usual Adult Dose for Acute Coronary Syndrome:
300 mg as an initial loading dose, followed by 75 mg orally once a day with or without food.
Aspirin therapy should be initiated and continued in combination with clopidogrel.
Usual Pediatric Dose for Platelet Aggregation Inhibition:
Note: Safety and efficacy have not been established in pediatric patients; optimal dose is not known; limited dosing information is available; further pediatric studies are needed.
Neonates and Infants up to 2 years: 0.2 mg/kg once daily was found to achieve a mean inhibition of platelet aggregation similar to adults receiving the recommended dose. This dose comes from the PICOLO study which included pediatric patients with a systemic-to-pulmonary artery shunt, intracardiac or intravascular stent, Kawasaki disease, or arterial graft; 79% of patients received concomitant aspirin; patients less than 2 kg and those born at less than 35 weeks gestational age were excluded (see Li, 2008).
Children over 2 years of age: Optimal dose is not established; some centers use the following: Initial dose: 1 mg/kg once daily; titrate to response; in general, do not exceed adult dose.
clopidogrel is an inhibitor of platelet aggregation.A variety of drug that inhibit platelet function have been shown to decrease morbid events in people with establish atherosclerotic cardiovascular disease as evidenced by strock or transient ischemic attacks.myocardial infarction or need for bypass or angioplasty.This indicates that platelets particiption in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.
Pharmacodynamics
Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Plavix. Repeated doses of 75 mg Plavix per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Plavix per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.
Metabolism
Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450
enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in Cmax and AUC, respectively.
Pharmacokinetics
Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
Elimination
Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.
Indication for used
Clopidogrel is used to prevent strokes and heart attacks in patients at risk for these problems. Clopidogrel is in a class of medications called antiplatelet drugs. It works by helping to prevent harmful blood clots that may cause heart attacks or strokes.
Side effects
Clopidogrel may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- excessive tiredness
- headache
- dizziness
- nausea
- stomach pain
- diarrhea
- nosebleed
Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:
- hives
- rash
- itching
- difficulty breathing or swallowing
- swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
- hoarseness
- black and tarry stools
- red blood in stools
- bloody vomit
- vomit that looks like coffee grounds
- unusual bleeding or bruising
- slow or difficult speech
- weakness or numbness of an arm or a leg
- vision loss
- fever
- shortness of breath
- fast heartbeat
- pale skin
- purple patches or bleeding under the skin
- confusion
- yellowing of the skin or eyes
Clopidogrel Dosing Information
Usual Adult Dose for Ischemic Stroke:
75 mg orally once a day with or without food.
Aspirin therapy should be initiated and continued in combination with clopidogrel.
Adult Dose for Myocardial Infarction:
75 mg orally once a day with or without food.
Aspirin therapy should be initiated and continued in combination with clopidogrel.
Usual Adult Dose for Acute Coronary Syndrome:
300 mg as an initial loading dose, followed by 75 mg orally once a day with or without food.
Aspirin therapy should be initiated and continued in combination with clopidogrel.
Usual Pediatric Dose for Platelet Aggregation Inhibition:
Note: Safety and efficacy have not been established in pediatric patients; optimal dose is not known; limited dosing information is available; further pediatric studies are needed.
Neonates and Infants up to 2 years: 0.2 mg/kg once daily was found to achieve a mean inhibition of platelet aggregation similar to adults receiving the recommended dose. This dose comes from the PICOLO study which included pediatric patients with a systemic-to-pulmonary artery shunt, intracardiac or intravascular stent, Kawasaki disease, or arterial graft; 79% of patients received concomitant aspirin; patients less than 2 kg and those born at less than 35 weeks gestational age were excluded (see Li, 2008).
Children over 2 years of age: Optimal dose is not established; some centers use the following: Initial dose: 1 mg/kg once daily; titrate to response; in general, do not exceed adult dose.
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Unknown - Wednesday 6 April 2011
