Ticlopidine

Last updated
Ticlopidine
Ticlopidine.svg
Ticlopidine ball-and-stick.png
Clinical data
Trade names Ticlid
AHFS/Drugs.com Monograph
MedlinePlus a695036
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out)
    Routes of
    administration
    By mouth
    ATC code
    Legal status
    Legal status
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability >80%
    Protein binding 98%
    Metabolism Hepatic
    Elimination half-life 12 hours (single dose)
    4–5 days (repeated dosing)
    Excretion Renal and fecal
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard 100.054.071 OOjs UI icon edit-ltr-progressive.svg
    Chemical and physical data
    Formula C14H14ClNS
    Molar mass 263.78 g·mol−1
    3D model (JSmol)
       (verify)

    Ticlopidine (trade name Ticlid) is an antiplatelet drug in the thienopyridine family which is an adenosine diphosphate (ADP) receptor inhibitor. Research initially showed that it was useful for preventing strokes and coronary stent occlusions. However, because of its rare but serious side effects of neutropenia and thrombotic thrombocytopenic purpura it was primarily used in patients in whom aspirin was not tolerated, or in whom dual antiplatelet therapy was desirable. With the advent of newer and safer antiplatelet drugs such as clopidogrel and ticagrelor, its use remained limited.

    Contents

    It was patented in 1973 and approved for medical use in 1978. [1]

    Medical uses

    Ticlopidine is FDA approved for the prevention of strokes and, when combined with aspirin, for patients with a new coronary stent to prevent closure. There are also several off-label uses, including acute treatment of myocardial infarction and unstable angina, peripheral vascular disease, prevention of myocardial infarctions, diabetic retinopathy, and sickle cell disease.

    Stroke

    Ticlopidine is considered a second-line option for the prevention of thrombotic strokes among patients who have previously had a stroke or TIA. Studies have shown that it is superior to aspirin in the prevention of death or future strokes. However, it also has more frequent and serious side effects compared to aspirin, so it is reserved for those patients that cannot take aspirin. [2]

    Heart disease

    When a patient needs to have a stent placed in one of the vessels around their heart, it is important that that stent stay open to keep blood flowing to the heart. Therefore, patients with stents must take medications after the procedure to help maintain that blood flow. Ticlopidine, taken together with aspirin, is FDA approved for this purpose, and in studies it has been shown to work better than aspirin alone or aspirin with an anticoagulant. [3] [4] However, ticlopidine’s serious side effects make it less useful than its cousin, clopidogrel. Current recommendations no longer recommend ticlopidine’s use. [5]

    Contraindications

    The use of ticlopidine is contraindicated in anyone with:

    Because of the increased risk of bleeding, patients taking ticlopidine should discontinue the medication 10–14 days before surgery. [6]

    Adverse effects

    The most serious side effects associated with ticlopidine are those that affect the blood cells, although these life-threatening complications are relatively rare. The most common side effects include: [6]

    Ticlopidine may also cause an increase in cholesterol, triglycerides, liver enzymes, and bleeding. [6]

    Hematological

    Use of ticlopidine has been associated with neutropenia, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia. Because of this risk, patients who are started on ticlopidine are typically monitored with blood tests to test their cell counts every two weeks for the first three months. [6]

    Pregnancy and lactation

    Ticlopidine is a FDA pregnancy risk category B. There have been no studies done in humans. Studies in rats show that high drug levels could cause toxicity in both mother and fetus, but there are no known birth defects associated with its use. [6]

    There have been no studies to test whether ticlopidine goes into breast milk. Studies in rats have shown that it is passed in rats’ milk. [6]

    Interactions

    Ticlopidine interacts with several classes of medications. It increases the antiplatelet effects of aspirin and other NSAIDs. [6] Taking ticlopidine at the same time as antacids decreases the absorption of ticlopidine. [6] Ticlopidine inhibits liver CYP2C19 [7] and CYP2B6 [8] and thus can affect blood levels of medications metabolized by these systems.

    Mechanism of action

    Ticlopidine is a thienopyridine which, when metabolized by the body, irreversibly blocks the P2Y12 component of the ADP receptor on the surface of platelets. Without ADP, fibrinogen does not bind to the platelet surface, preventing platelets from sticking to each other. [6] By interfering with platelet function, ticlopidine prevents clots from forming on the inside of blood vessels. [9] Anti-platelet effects start within 2 days and reach their maximum by 6 days of therapy. Ticlopidine’s effects persist for 3 days after discontinuing ticlopidine although it may take 1–2 weeks for platelet function to return to normal, as the medication affects platelets irreversibly. Therefore, new platelets must be formed before platelet function normalizes. [6]

    Pharmacokinetics

    Ticlopidine is ingested orally with 80% bioavailability with rapid absorption. Even higher absorption can occur if ticlopidine is taken with food. It is metabolized by the liver with both renal and fecal elimination. Clearance is nonlinear and varies with repeated dosing. After the first dose the half life is 12.6 hours, but with repeated dosing the maximum half life is 4–5 days. Clearance is also slower in the elderly. The drug is 98% reversibly bound to proteins. [6]

    Chemical properties

    Ticlopidine's systemic name is 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. Its molecular weight is 263.786 g/mol. It is a white crystalline solid. It is soluble in water and methanol and somewhat soluble in methylene chloride, ethanol, and acetone. It self buffers in water to a pH of 3.6. [6]

    History

    Ticlopidine was discovered in the 1970s in France by a team led by Fernand Eloy and including Jean-Pierre Maffrand at Castaigne SA that was trying to discover a new anti-inflammatory medication. Pharmacology developers noted that this new compound had strong anti-platelet properties. [10] Castaigne was acquired by Sanofi in 1973. [11] Starting in 1978 the drug was marketed in France under the brand name Ticlid for people at high risk for thrombotic events, who had just come out of heart surgery, were undergoing hemodialysis, had peripheral vascular disease, or who were otherwise at risk for strokes and ischemic heart disease. [10]

    Ticlopidine was brought to market in the US by Syntex, which got the drug approved in 1991. [12] Syntex was acquired by the Roche group in 1994. [13] The first generic ticlopidine hydrochloride was FDA approved in 1999. [14] As of April 2015, Roche, Caraco, Sandoz, Par, Major, Apotex, and Teva had discontinued generic ticlopidine and no ticlopidine preparations were available in the US. [15]

    Research

    Soon after its release, studies regarding ticlopidine found it had the potential to be helpful for other diseases including peripheral vascular disease, [16] diabetic retinopathy, [17] and sickle cell disease. [18] However none had enough evidence for FDA approval. Due to the blood cell side effects associated with ticlopidine, researchers for treatments for these conditions have turned to other avenues.

    Related Research Articles

    Aspirin medication used to reduce pain, fever, and inflammation

    Aspirin, also known as acetylsalicylic acid (ASA), is a medication used to reduce pain, fever, or inflammation. Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. Aspirin given shortly after a heart attack decreases the risk of death. Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. It may also decrease the risk of certain types of cancer, particularly colorectal cancer. For pain or fever, effects typically begin within 30 minutes. Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and works similarly to other NSAIDs but also suppresses the normal functioning of platelets.

    Coronary artery disease Disease characterized by plaque building up in the arteries of the heart

    Coronary artery disease (CAD), also known as coronary heart disease (CHD) or ischemic heart disease (IHD), involves the reduction of blood flow to the heart muscle due to build-up of plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. Types include stable angina, unstable angina, myocardial infarction, and sudden cardiac death. A common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. Usually symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.

    A transient ischemic attack (TIA), commonly known as a mini-stroke, is a brief episode of neurological dysfunction caused by loss of blood flow (ischemia) in the brain, spinal cord, or retina, without tissue death (infarction). TIAs have the same underlying mechanism as ischemic strokes. Both are caused by a disruption in blood flow to the brain, or cerebral blood flow (CBF). The definition of TIA was classically based on duration of neurological symptoms. The current widely accepted definition is called "tissue-based" because it is based on imaging, not time. The American Heart Association and the American Stroke Association (AHA/ASA) now define TIA as a brief episode of neurological dysfunction with a vascular cause, with clinical symptoms typically lasting less than one hour, and without evidence of infarction on imaging.

    An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.

    Anticoagulant class of drugs

    Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart-lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.

    Clopidogrel medication that is used to reduce the risk of heart disease and stroke in those at high risk.

    Clopidogrel, sold under the trade name Plavix among others, is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following the placement of a coronary artery stent. It is taken by mouth. Onset of effects is about two hours and lasts for five days.

    Dipyridamole anticoagulant drug

    Dipyridamole is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation when given chronically and causes blood vessel dilation when given at high doses over a short time.

    Prasugrel drug that acts as a platelet inhibitor and is used to prevent formation of blood clots.

    Prasugrel (trade name Effient in the US, Australia and India, and Efient in the EU) is a drug used to prevent formation of blood clots. It is a platelet inhibitor and an irreversible antagonist of P2Y12 ADP receptors and is of the thienopyridine drug class. It was developed by Daiichi Sankyo Co. and produced by Ube and currently marketed in the United States in cooperation with Eli Lilly and Company.

    Eptifibatide chemical compound

    Eptifibatide, is an antiplatelet drug of the glycoprotein IIb/IIIa inhibitor class. Eptifibatide is a cyclic heptapeptide derived from a disintegrin protein found in the venom of the southeastern pygmy rattlesnake. It belongs to the class of the arginin-glycin-aspartat-mimetics and reversibly binds to platelets. Eptifibatide has a short half-life. The drug is the third inhibitor of GPIIb/IIIa that has found broad acceptance after the specific antibody abciximab and the non-peptide tirofiban entered the global market.

    Drug-eluting stent peripheral or coronary stent (a scaffold) placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation.

    A drug-eluting stent (DES) is a peripheral or coronary stent placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation. This prevents fibrosis that, together with clots (thrombi), could otherwise block the stented artery, a process called restenosis. The stent is usually placed within the peripheral or coronary artery by an interventional cardiologist or interventional radiologist during an angioplasty procedure.

    The history of invasive and interventional cardiology is complex, with multiple groups working independently on similar technologies. Invasive and interventional cardiology is currently closely associated with cardiologists, though the development and most of its early research and procedures were performed by diagnostic and interventional radiologists.

    Coronary stent medical apparatus implanted into coronary arteries

    A coronary stent is a tube-shaped device placed in the coronary arteries that supply blood to the heart, to keep the arteries open in the treatment of coronary heart disease. It is used in a procedure called percutaneous coronary intervention (PCI). Coronary stents are now used in more than 90% of PCI procedures. Stents reduce angina and have been shown to improve survivability and decrease adverse events in an acute myocardial infarction.

    Vorapaxar chemical compound

    Vorapaxar is a thrombin receptor antagonist based on the natural product himbacine, discovered by Schering-Plough and developed by Merck & Co.

    Ticagrelor platelet aggregation inhibitor

    Ticagrelor (trade name Brilinta, Brilique, and formerly Possia) is a pharmaceutical drug used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor. The drug is produced by AstraZeneca.

    Terutroban chemical compound

    Terutroban is an antiplatelet agent developed by Servier Laboratories. It is a selective thromboxane prostanoid (TP) antagonist and is an orally active drug in clinical development for the secondary prevention of acute thrombotic complications.

    Thienopyridine

    Thienopyridines are a class of selective, irreversible ADP receptor/P2Y12 inhibitors used for their anti-platelet activity.

    Cangrelor chemical compound

    Cangrelor (trade name Kengreal in the US and Kengrexal in Europe) is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.

    Adenosine diphosphate (ADP) receptor inhibitors are a drug class of antiplatelet agents, used in the treatment of acute coronary syndrome (ACS) or in preventive treatment for patients who are in risk of thromboembolism, myocardial infarction or a stroke. These drugs antagonize the P2Y12 platelet receptors and therefore prevent the binding of ADP to the P2Y12 receptor. This leads to a decrease in aggregation of platelets, prohibiting thrombus formation. The P2Y12 receptor is a surface bound protein found on blood platelets. They belong to G protein-coupled purinergic receptors (GPCR) and are chemoreceptors for ADP.

    Management of acute coronary syndrome is targeted against the effects of reduced blood flow to the afflicted area of the heart muscle, usually because of a blood clot in one of the coronary arteries, the vessels that supply oxygenated blood to the myocardium. This is achieved with urgent hospitalization and medical therapy, including drugs that relieve chest pain and reduce the size of the infarct, and drugs that inhibit clot formation; for a subset of patients invasive measures are also employed. Basic principles of management are the same for all types of acute coronary syndrome. However, some important aspects of treatment depend on the presence or absence of elevation of the ST segment on the electrocardiogram, which classifies cases upon presentation to either ST segment elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome (NST-ACS); the latter includes unstable angina and non-ST elevation myocardial infarction (NSTEMI). Treatment is generally more aggressive for STEMI patients, and reperfusion therapy is more often reserved for them. Long-term therapy is necessary for prevention of recurrent events and complications.

    Apixaban Anticoagulant drug, a direct inhibitor of factor X, also used in the prevention of venous thromboembolism

    Apixaban, sold under the brand name Eliquis among others, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. It is taken by mouth.

    References

    1. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 453. ISBN   9783527607495.
    2. Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, Kamm B (24 August 1989). "A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group". N Engl J Med. 321 (8): 501–507. doi:10.1056/nejm198908243210804. PMID   2761587.
    3. Schomig L, Neumann FJ, Kastrati A, et al. (1996). "A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents". N Engl J Med. 334 (17): 1084–1089. doi:10.1056/nejm199604253341702. PMID   8598866.
    4. Leon MB1, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE (3 December 1993). "A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators". N Engl J Med. 339 (23): 1665–1671. doi:10.1056/nejm199812033392303. PMID   9834303.CS1 maint: multiple names: authors list (link)
    5. American College of Cardiology/American Heart Association Task Force on Practice Guidelines (2014). "2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes". Circulation. 130 (25): e344–426. doi:10.1161/CIR.0000000000000134. PMID   25249585.
    6. 1 2 3 4 5 6 7 8 9 10 11 12 Roche Laboratories, Inc. (2001). "Ticlid (ticlopidine) package insert" (PDF). US Food & Drug Administration.
    7. Ha-Duong NT, Dijols S, Macherey, AC (2001). "Ticlopidine as selective mechanism-based inhibitor of human cytochrome P450 2C19". Biochemistry. 40 (40): 12112–12122. doi:10.1021/bi010254c.CS1 maint: multiple names: authors list (link)
    8. Turpeinen M, Tolonen A, Uusitalo J, et al. (2005). "Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation". Clin Pharmacol Ther. 77 (6): 553–559. doi:10.1016/j.clpt.2005.02.010. PMID   15961986.
    9. Katzung B, Masters S, Trevor A (2012). Basic and Clinical Pharmacology, 12th ed. pp. Chapter 34: Drugs Used in Disorders of Coagulation.
    10. 1 2 Maffrand, JP (2012). "The story of clopidogrel and its predecessor, ticlopidine: Could these major antiplatelet and antithrombotic drugs be discovered and developed today?". Comptes Rendus Chimie. 15 (8): 737–743. doi:10.1016/j.crci.2012.05.006.
    11. Aftalion, Fred (2001). A History of the International Chemical Industry. Chemical Heritage Foundation. p. 296. ISBN   9780941901291.
    12. Flores-Runk, P; Raasch, RH (September 1993). "Ticlopidine and antiplatelet therapy". The Annals of Pharmacotherapy. 27 (9): 1090–8. doi:10.1177/106002809302700915. PMID   8219445.
    13. Freudenheim, Milt (3 May 1994). "Roche Set To Acquire Syntex". New York Times.
    14. "Press release: Apotex First To Market Generic Version Of Ticlid®". July 6, 1999.
    15. "Ticlopidine Tablets". Resolved Shortages Bulletin. American Society of Health-System Pharmacists. April 1, 2015. Retrieved 3 June 2015.
    16. Kirstein P, Jogestrand T, Johnsson H, et al. (1980). "Antiaggregatory, physiological and clinical effects of ticlopidine in subjects with peripheral atherosclerosis". Atherosclerosis. 36 (4): 471–480. doi:10.1016/0021-9150(80)90240-3.
    17. The TIMAD Study Group (1990). "Ticlopidine treatment reduces the progression of nonproliferative diabetic retinopathy". Arch Ophthalmol. 108 (11): 1577. doi:10.1001/archopht.1990.01070130079035.
    18. Cabannes R, Lonsdorfer J, Castaigne JP, et al. (1984). "Clinical and biological double-blind study of ticlopidine in preventive treatment of sickle cell disease crises". Agents Actions.