Pharmacology of Platelets and Blood Clotting PDF

Blockeers of plaatelet ADP recepto ors: (Ticlop pedine, clo opidogrel, prasugre el)  Theese drugss irreverrsibly inhibit the binnding of AD DP to its receptorss on pla atelets andd, therebyy, inhibit the activation of...

Blockeers of plaatelet ADP recepto ors: (Ticlop pedine, clo opidogrel, prasugre el)  Theese drugss irreverrsibly inhibit the binnding of AD DP to its receptorss on pla atelets andd, therebyy, inhibit the activation of the glyccoprotein IIb/IIIa receeptors required for plattelets to bind to fibrin nogen andd to each other. o  Cloopidogrel is i approve ed for propphylaxis off thrombossis in bothh cerebrov vascular andd cardiovasscular dise ease (e.g. coronary artery dise ease, coro onary angio oplasty, periipheral vasscular diseease, etc.). The mainttenance do ose is 75 mmg/d orally y.  Clopidogrel iss a prodru ug, and its therapeuttic efficacyy relies enttirely on its s active mettabolite. So ome people have ge enetic defic ciency in th he enzymees that mettabolize pidogrel; they are calle clop ed “poor m metabolizerrs”, and caannot beneffit from thiss drug.  Ticlopedine has h been largely rreplaced by b cloped dogrel beccause of serious advverse effec cts (neutroppenia and bleeding)). Clopidog grel has feewer incidence of thesse effects. Blockeers of pla atelet gly ycoprotein n IIb/IIIa receptors: (Abcixiimab, eptiifibatide, tirofiban) t  Activation of this recep ptor compllex is the “final com mmon pathhway” for platelet agggregation and a bindinng with fib brinogen. Persons P la acking thiss receptor have a blee eding disorder called d Glanzman nn’s throm mbasthenia a.  Abc ciximab is the Fab fragment o of a monoc clonal antib binds to gpIIb/IIIa body that b andd blocks binding of platelets to fibrinogenn.  Epttifibatide is a small syntheticc peptide that com mpetitively blocks gpIIb/IIIa receeptor.  Tiro ofiban is a peptide ofo low MW that binds s to the gpIIIb/IIIa receeptor.  Theese drugs have been n approvedd for use in patientss undergo ing percuttaneous coroonary interrvention, fo or unstable e angina, and a for pos st-MI. Dipyridamole  Dipyyridamole inhibits phosphodi p zyme → ↑ cGMP → VD and iesterase (PDE) enz inhibition of platelet p acttivity. It alsso inhibits o adenossine into platelets s uptake of p andd RBCs lea ading to ex xtracellular accumula ation and prolongatio p on of its action.  Thee use of dipyridamo d ole as an antithromb botic agennt is limiteed to prop phylaxis (com mbined witth warfarinn) in patien nts with proosthetic (m mechanicaal) heart va alves. 215  █ DRUGS USED IN BLEEDING DISORDERS (HEMOSTATIC AGENTS) ▌Systemic agents – Vitamin K: essential for synthesis of factors II, VII, IX, X by the liver. – Vitamin C and rutin: preserve the integrity of the vascular wall. – Fresh blood or plasma transfusion: as sources of coagulation factors. – Plasma fractions: – Thromboplastin (factor III): prepared from mammalian tissues. – Antihemophilic globulin (factor VIII): given in hemophilia A. – Calcium (factor IV): as a coagulation factor. – Aminocaproic acid and tranexamic acid: inhibitors of fibrinolytic system. – Ethamsylate (Dicynone): given i.m. to reduce capillary bleeding. ▌Local agents – Physical methods: application of pressure, cooling or heat coagulation. – Vasoconstrictor drugs: e.g. adrenaline nasal pack in epistaxis. – Astringents: drugs which precipitate surface proteins e.g. alum sulphate. – Thrombin and thromboplastin: applied on the bleeding surface as powders. – Fibrin and fibrinogen: available as dried sheets and used in surgery. – Oxidized cellulose: it forms an adhesive mass on the bleeding surface. – Sclerosing agents: chemicals that cause thrombosis in veins and permanent obliteration, e.g. ethanolamine oleate (given i.v. for varicose veins). Vitamin K  Vitamin K1 (phytomenadione) is a naturally occurring fat-soluble vitamin present in green vegetables. It is available clinically in oral and parenteral forms.  Vitamin K2 is synthesized by intestinal bacteria.  Both vitamins K1 and K2 require bile salts for absorption from the intestine. Mechanism of action: Vitamin K is required for posttranslational modification of clotting factors II, VII, IX, and X by liver cells. Therapeutic uses  To reverse bleeding episodes caused by overdose of warfarin, salicylates, and oral hypoglycemic drugs.  To correct vitamin deficiency caused by dietary deficiency, or in patients receiving oral antibiotics.  To prevent hypothrombinemia of the newborn: all newborns should routinely receive 1–2 mg of vitamin K directly after birth (especially in premature infants). 216 Advers s: parenteral vitamin K1 is diss se effects solved in oil; o rapid ii.v. administration can cau use dyspnnea, chest pain, or evven death. N.B.. severe hepatic failure f is associate ed with bleeding b teendency (due ( to redu uced synthesis of clo otting factoors) that do oes not res spond to vvitamin K. Plasm ma fractions  Deficiencies in plasma a coagulat ion facttors cann cause e bleedinng. Spoontaneous bleeding occurs wh hen facttor activity is less than 5–10% % of norrmal. Factor VIII deficien ncy (classic hemo ophilia, or hemophilia h a A) andd factor IX X deficienccy (Christmmas diseease, or hemophilia h a B) accou unt for the mosst commo on herita able coaagulation defects.  Plassma prottein prepa arations a are avaailable for treatmen nt of the ese disoorders. The ey are admministered i.v.  Plassma fractions are frrequently prepared from bloo od or plassma pooleed from mulltiple indivviduals; thus, they a are assoc h high riskk of exposure to ciated with ection (he infe epatitis andd HIV). Fo or this reason, recoombinant preparatioons are recoommended d wheneve er possible e. Inhibittors of fib brinolysis s: (Amino ocaproic acid a and trranexamic c acid) Aminocaproic acida is a synthetic agent tha at competitively inhi bits plasm minogen activatiion. Trane examic aciid is more potent ana alogue of aminocapr a roic acid. Therap peutic use es  To prevent bleeding frrom tissuees rich in plassminogen activators e.g. lung, prostatic surggery, meno orrhagia, and a ocular trauma.  Prophylaxis for rebleeding r from intrracranial aneurysm. a.  As a adjunctive therapy in n hemophiilia.  To stop blee eding caus sed by tox xicity of fibrrinolytic drrugs. 217