Anti platelet drugs

Anti platelet drugs

• 1.
  M.Asiyabi M.Pharm-1st year Department ofpharmacology
• 2.
  Historical background • Plateletswere discovered by G.Bizzozero in 1882. • But, drug industry did not recognise them as viable drug targets till 1960. • Initially, researchers focused on clotting time and also in thrombocytopenia. • In 1960, focus shifted to interaction of platelets with adhesion and aggregation.
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  Terminologies • Thrombus :a blood clot formed in situ within the vascular system of the body and impeding blood flow. • Embolus : a blood clot, air bubble, piece of fatty deposit, or other object which has been carried in the bloodstream cause an embolism. • Venous thrombosis : a blood clot (thrombus) that forms within a vein • Deep vein thrombosis : a blood clot in the deep veins of the leg • Pulmonary embolism : a blood clot in the lungs. • Arterial thrombosis : a blood clot that develops in an artery
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  Etiology • Arterial andvenous thromboses are major causes of morbidity and mortality rates. • Deep-vein thrombosis (DVT) leads to pulmonary embolism (PE). • This triggers platelet aggregation and fibrin formation leading to generation of a platelet- rich thrombus that can temporarily or permanently occlude blood flow.
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  • Arterial thrombiare rich in platelets because of the high shear in the injured arteries. • In contrast, venous thrombi (low shear condition) contain relatively few platelets and are predominantly composed of fibrin and trapped red cells.
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  Action of Thrombin •Release from endothelium (NO, PGI2 , von vilebrand etc) • Prothrombin to thrombin • Activation of platelets • Factor V to Va and factor VIII to VIIIa • Fibrinogen to fibrin
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  Epidemiology • > 2.5million of deep vein thrombosis per year • > 600,000 cases of pulmonary embolism every year • > 50,000 deaths from pulmonary embolism • > 11,000 post surgical PE every year
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  Rationale for Anti-thromboticdrugs Vascular injury Platelet adherance and activation Thrombin generation and fibrin formation Plasmin generation and fibrinolysis Reduce risk factors Platelet inhibitors Anti coagulants Fibrinolytic drugs THROMBOGENESIS THERAPHY
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  1 • ANTI-PLATELET DRUGS 2 •ANTI-COAGULANTS 3 • FIBRINOLYTICS ANTI-THROMBOTIC DRUGS
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  TREATMENT STRATEGY • Strategiesto inhibit or treat arterial thrombosis focus mainly on antiplatelet agents. • Anticoagulants are the mainstay of prevention and treatment of venous thromboembolism (because fibrin is the predominant component) • Fibrinolytic therapy is used in selected patients with venous thromboembolism.(Massive PE)
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  ANTI - PLATELETAGENTS “Drugs which interfere with platelet function and are useful in prophylaxis of thromboembolic disorders”
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  ROLE OF PLATELETS
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  Antiplatelet drugs targetvarious steps in this process.
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  Anti-platelet drugs Acetylsalicylic acid (aspirin) P2Y12 antagonists GPIIb/IIIa antagonists Dipyridamole
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  Newer anti-platelet drugs •Ticagrelor • Thrombin Receptor Blockers : Vorapaxar
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  ASPIRIN (Acetyl salicylic acid) •The most widely used antiplatelet agent worldwide is aspirin. • Maximal effective dose : 50-320 mg • At high doses (1 g/d), it also inhibits COX-2 (responsible for synthesis of prostacyclin, a potent inhibitor of platelet aggregation) • So, Higher doses are potentially less efficacious and also increase toxicity, especially bleeding.
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  Aspirin blocks productionof TxA2 by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1). ASPIRIN – MECHANISM OF ACTION
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  Side Effects • Doserelated side effects - Dyspepsia - Erosive gastritis - Peptic ulcers with bleeding and perforation. • Hepatic and renal toxicity are observed with aspirin overdose • The risk of bleeding is increased when used with warfarin.
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  Major drawbacks • Allergicreactions - History of aspirin allergy characterized by bronchospasm. • Is not a very effective antithrombotic drug but is widely used because of its ease of use • Lack of response in some patients (aspirin resistance) • The irreversible platelet inhibition.
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  Dipyridamole Properties other thananti-platelet activity : • Dipyridamole is a potent coronary vasodilator. • It has minimal effect on BP and cardiac work. MECHANISM OF ACTION ON NEXT SLIDE
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  - It interfereswith platelet function by decreasing the metabolism of cAMP to 5’ AMP By inhibiting cyclic nucleotide phosphodiesterases ( involved in metabolism of cAMP). - It also inhibits Adenosine deaminases
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  Therapeutic uses • Thedrug has little or no benefit as an antithrombotic agent. • So It is used in combination with warfarin. • In the prophylaxis of coronary and cerebral thrombosis of post-MI and post-stroke patients. • In patients with Prosthetic valves (artificial heart valve) - it inhibits embolization. • Dosage : 150 to 300 mg given BD
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  Adverse effects • Exacerbationof Angina • Headache • Tachycardia • GI distress. DRAWBACKS : 1. Dipyridamole also has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease; 2. chest pain may be aggravated in patients with coronary artery disease who are receiving dipyridamole
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  Ticlopidine and Clopidogrel •ADP antagonists, inhibit binding of Adenosine di phosphate (ADP) to its receptors irreversibly • Also Inhibit fibrinogen induced platelet aggregation with out modifying GPIIb/IIIa • Synergistic action with aspirin • Both are prodrugs have long duration of antiplatelet effect • Clopidogrel a congener of ticlodipine is safer and better tolerated.
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  MOA - ADPAntagonists
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  Adverse effects Ticlopidine (Dose: 250 mg BD) – Diarrrhoea, vomiting, abdominal pain – Headache, tinnitus, skin rash – Bleeding, neutropenia, thrombocytopenia Clopidogrel (Dose : 75 mg OD) – Implantation bleeding – Less bone marrow toxicity – Diarrhoea, epigastric pain, rashes
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  Clopidogrel resistence • Thisvariability is because of genetic polymorphisms in the Cytochrome P450 (CYP2C19*2) isoenzymes involved in the metabolic activation of clopidogrel. • This is important because 25% of whites, 30% of African Americans, and 50% of Asians carry the loss- of-function allele. • This will render them resistant to clopidogrel. • So to such patients , prasugrel or newer P2Y12 inhibitors may be better choices.
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  Prasugrel • It isalso prodrug. • Its onset of action is more rapid than that of ticlopidine or clopidogrel. • It produces greater and more predictable inhibition of ADP-induced platelet aggregation. • It has prolonged effect after discontinuation • Therefore problem araises if patients require urgent surgery.
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  Cont… • Contraindication :those with a history of cerebrovascular disease (high risk of bleeding). • Caution : in patients weighing <60 kg or in those with renal impairment. • Dose : loading dose is 60 mg, and is given once daily at a dose of 10 mg.
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  Glycoprotein IIb/IIIa Inhibitors •Glycoprotein IIb/IIIa is a platelet-surface integrin. • Glycoprotein IIb/IIIa is inactive on resting platelets. • It undergoes a conformational transformation when platelets are activated by thrombin, collagen, or TxA2 which endows GP with the capacity to serve as a receptor for fibrinogen and von Willebrand factor. • Thus, inhibitors of this receptor are potent antiplatelet agents.
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  Drugs (GP IIa/IIIbinhibitors) • Newer potent platelet aggregation inhibitor -Abciximab, -Eptifibatide and -Tirofiban
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  Abciximab • It isis the Fab fragment of a humanized monoclonal antibody. • It also binds to the vitronectin receptor on platelets, vascular endothelial cells etc.. (Vitronectin is a GP present in serum) • Dose : 0.25-mg/kg bolus followed by 0.125 g/kg/min for 12 hours. • Side effect : Bleeding, Haemorrhage, Thrombocytopenia, paralytic ileus, constipation. • Drawback : Expansive
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  Newer Anti-Platelets (Ticagrelor) •It is an orally active, reversible inhibitor of Purinergic receptor (P2Y12) – a G protein coupled receptor. • Dose : 90 mg tablets are available. • When compared with clopidogrel, ticagrelor produced a greater reduction in cardiovascular death, MI, and stroke. • It has a more rapid onset and offset of action.
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  Vorapaxar • It isan orally active, high-affinity, potent and competitive reversible antagonist of protease activated receptor (PAR-1) • So it blocks thrombin-mediated platelet activation. • Dose :Tablet 2.08 mg with Aspirin/ Clopidogrel daily. • Indications : To reduce thrombotic cardiovascular events in patients. • Adverse effect : Bleeding, depression, anemia.
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  Drug screening methods 1.In-vitromethods Assay methods Washed platelet method Whole blood aggregometry Platelet function analyser 2.In-vivo methods Model of corotid artery occlusion in dogs Photochemically induced thrombosis model in rats Studies of anti- platelet efficacy in rhesus monkeys Anti-platelet efficacy in baboons 3.Ex-vivo method
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  Assay method –Born’s test (Turbidimetry) 1. Selection of healthy volunteer blood donors 2. Preparation of platelets : Fresh blood from male rabbit centrifuged at 250g for 10 mins to obtain platelet-rich-plasma (PRP) 3. Assay method : - Drug conc : 1-100 µM - incubated with 0.25ml of platelet rich plasma for 1min - followed by activation of platelet with various agonist - aggregation induced by ADP (100 µm), collagen or thrombin
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  Cont… • The inhibitionof aggregation is expressed as the percentage of the maximal rate of aggregation observed in the absence of antagonists.
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  Platelet function analyser(PFA)
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  PFA -procedure • Bloodsample is drawn and stored at RT with citrated buffer solution. • 800 µL containing test drug is placed into a catridge. • The test catridges simulate an injured blood vessel in which the membrane coated with type I collagen or ADP catridge. • Blood is pipetted and aspirated thro a capillary with negative pressure and thereby shear forces is produced.
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  cont…. • Platelet aggregationis produced. • Finally, a platelet plug occludes the apperture. • The time measurewd in secs from beginning of test untill formation of aggregates is called closure time (measure of over all function of platelets)
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  Ex-vivo method • Acidsoluble collagen (100 µg/kg) is injected into the aortic arch of rabbits via carotid artery. • Platelet count is performed on blood withdrawn subsequent to collagen administration. • The test drug is administered to the animal before the collagen injection.
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  Photochemically induced thrombosis modelin rats • Requirements : - Animal : male wistar rats (230-320 gms) - Anesthetic : Penobarbitol sodium - Test drug • Jugular vein cannulation • Microvessels in the mesentry are observed under trans illumination with halogen lamp. • Thrombus formation is induced in the microvessels by filtered light of wavelength 420-490 nm.
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  Procedure • Test drugadministered as i.v bolus into jugular vein of a rat. • Irradiation is started after 1 mins and flourescein sodium (2.5% w/v) is injected. • Whole process is monitored with TV camera • The time when the thrombus begins to form (time of initiation) and time when blood flow completely stops (time of occlusion) are used to determine ant-platelet activity. • Rats are sacrificed at the end of experiment by overdose of KCl.