Clopidogrel; Uses, Dosage, Side Effects, Drug Interactions

Clopidogrel, an antiplatelet agent structurally and pharmacologically similar to ticlopidine, is used to inhibit blood clots in a variety of conditions such as peripheral vascular disease, coronary artery disease, and cerebrovascular disease. It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent (dual antiplatelet therapy). It is taken by mouth. The onset of effects is about 2 hours and lasts for 5 days.

Mechanism of Action of Clopidogrel

The active metabolite of clopidogrel prevents the binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. he drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in the aggregation of platelets and cross-linking by the protein fibrin. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of clopidogrel.

or

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.

Indications of Clopidogrel

• Ischemic Stroke
• Heart attack
• Atherosclerosis
• Stroke, 
• Myocardial infarction, 
• Established peripheral arterial disease.
• Cardiovascular events
• Acute coronary syndrome, prophylaxis
• Acute coronary syndrome
• Ischemic Stroke, prophylaxis
• Percutaneous coronary intervention
• Peripheral arterial disease
• Platelet aggregation inhibition
• Transient ischemic attack

Treatment with clopidogrel or a related drug is recommended by the American Heart Association and the American College of Cardiology for people who:

Present for treatment with a myocardial infarction with ST-elevation including

• A loading dose is given in advance of percutaneous coronary intervention (PCI), followed by a full year of treatment for those receiving a vascular stent
• A loading dose given in advance of fibrinolytic therapy continued for at least 14 days

Present for treatment of a non-ST elevation myocardial infarction or unstable angina

• Including a loading dose and maintenance therapy in those receiving PCI and unable to tolerate aspirin therapy
• Maintenance therapy for up to 12 months in those at medium to high risk for which a noninvasive treatment strategy is chosen

In those with stable ischemic heart disease, treatment with clopidogrel is described as a “reasonable” option for monotherapy in those who cannot tolerate aspirin, as is treatment with clopidogrel in combination with aspirin in certain high-risk patients.

Therapeutic Indications of Clopidogrel

• For the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease. Secondary prevention of atherothrombotic eventsClopidogrel is indicated in
• Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
• Adult patients suffering from acute coronary syndrome
• Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).
• ST-segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy. Prevention of atherothrombotic and thromboembolic events in atrial fibrillation
• In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
• Secondary prevention of atherothrombotic events

Clopidogrel is indicated in

Clopidogrel is indicated in

Contra-Indications of Clopidogrel

• Increased risk of bleeding due to clotting disorder
• Increased risk of bleeding
• Retinal hemorrhage
• Hemorrhage within the skull
• Thrombotic thrombocytopenic purpura
• Acute hemorrhage
• Stomach or intestinal ulcer
• Bleeding of the stomach or intestines
• Recent operation
• Poor metabolizer
• Acquired hemophilia
• Intermediate metabolizer
• Chronic kidney disease stage 3A (moderate)
• Chronic kidney disease stage 3B (moderate)
• Chronic kidney disease stage 5 (failure)

Dosage of Clopidogrel

Strengths: 75 mg; 300 mg

Acute Coronary Syndrome

Unstable Angina (UA)/Non-ST-Elevation Myocardial Infarction (NSTEMI)

• Loading dose: 300 mg orally once
• Maintenance dose: 75 mg orally once a day
• Duration of therapy: Optimal duration unknown.

ST-Elevation Myocardial Infarction (STEMI)

• Loading dose: 300 mg orally once (OPTIONAL)
• Maintenance dose: 75 mg orally once a day, with or without thrombolytics
• Duration of therapy: Optimal duration unknown.

Ischemic Stroke

• 75 mg orally once a day

Myocardial Infarction

• 75 mg orally once a day

Peripheral Arterial Disease

• 75 mg orally once a day

Side Effects of Clopidogrel

The most common

• Upper respiratory tract infection
• Chest pain
• Headache
• Joint painPain
• Dizziness
• Nausea and vomiting
• Severe stomach ache
• epigastric pain,
• diarrhoea,
• anorexia,
• flatulence,
• headache,
• dizziness,
•  fainting, fast or pounding heartbeats;

More common

• Chest pain
• collection of blood under the skin
• Severe stomach ache
• Severe diarrhea
• Mouth sores
• Vaginal thrush
• Skin rash
• Headache
• Ringing or buzzing in the ears
• Decreased appetite
• deep, dark purple bruise
• itching, pain, redness, or swelling
• pain in general
• red or purple spots on the skin, varying in size from pinpoint to large bruises

Less common

• Nosebleed
• painful or difficult urination
• shortness of breath
• vomiting of blood or material that looks like coffee grounds
• Black, tarry stools
• blistering, flaking, or peeling of the skin
• blood in the urine or stools
• confusion
• fever, chills, or sore throat
• headache (sudden, severe)
• nausea or vomiting
• stomach pain (severe)
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising

Drug Interactions Clopidogrel

Clopidogrel may interact with following drugs, supplements & may decrease the efficacy of the drug

• antacids (e.g., aluminum hydroxide, calcium carbonate, magnesium hydroxide)
• “azole” antifungals (e.g., fluconazole, ketoconazole, voriconazole)
• bortezomib
• bupropion
• calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
• cimetidine
• dasatinib
• glucosamine
• heparin
• low molecular weight heparins (e.g., dalteparin, enoxaparin, tinzaparin)
• macrolide antibiotics (e.g., clarithromycin, erythromycin)
• nonsteroidal anti-inflammatories (NSAIDs; e.g., ibuprofen, diclofenac, ketorolac, naproxen)
• proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole)
• selegiline
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
• warfarin

Pregnancy & Lactation Clopidogrel  

 FDA Pregnancy Category B

Pregnancy

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