pharma fouda 2_p113-117.pdf

Part 2 2: Dru ugs affe ecting he emostas sis █ Basiic inform mation stasis is th Hemos h...

Part 2 2: Dru ugs affe ecting he emostas sis █ Basiic inform mation stasis is th Hemos he spontan neous arresst of bleed ding from damaged d b blood vess sel. ▌The c coagulatiion syste em: It conssists of a number of plasma a proteinns (facto ors). Eac ch factorr activatees anothe er till acttivation off fibrinog gen to formm fibrin. Activation cascad de is done e through 2 systemms: the inttrinsic sys stem (can n be mon nitored by the activaated partia al throbop plastin tim me “APTT””) and the e extrinssic system m (can be monitored d by protthrombin time). Preven ntion of clo otting:  Plassma conttains a number n off protteins thatt normally y preventt clottting thro ough inhibition off clottting factors (e.g. antithrombin n III).  Hepparin activvates antith hrombin III thuss inhibits ac ctivation of factors IX, X, XI, and XII.  Oraal anticoag gulants inh hibit synthhesis of clo otting facto ors by the l iver. Dissolu ution of bllood clots s:  Theere are oth a proteinss that can dissolve blood clotts (i.e. fibrrinolytic her plasma systtem e.g. plasmin).  The ere are som me drugs that t activa ate plasmin nogen to form the acctive plasm min and thuss enhancee fibrinolysis (e.g. stre eptokinas se, urokina ase, etc.).  Amminocaproiic acid is ana inhibitorr of fibrinolysis. ▌Drug gs can afffect hemo ostasis a and throm mbosis through:  By modifying the integriity of the vvessel wall.  By modifying blood coa agulation (clot forma ation).  By modifying platelet adhesion an nd activation.  By modifying fibrinolysis. 208 █ DRU UGS THAT T PREVEN NT COAGU ULATION (ANTICOA ( AGULANTS S) Heparin Warfarin (Ora l anticoag gulant) Source e& Naatural sulfate ed polysac ccharide Synthetic cuomaarin compound chemis stry preesent in maast cells & c carries –ve chaarge Coommercial preparation p ns are de- rive ed from bovine lung o or porcine intesttinal extractts Absorp ption  No becaus se it precip pitates by  Good (bioavaailability is 100%). gastric HC Cl.  Can n cross BB BB and pla acenta. Distribttion  Cannot crross BBB o or placenta a.  Its action depends d o on the pres s-  Wa arfarin inhib bits vitamin K ence of a natural clo otting inhibb- epooxide redu uctase enz zyme itor called heparin co ofactor in the liver leaading to in nhibition (antithrom mbin III) in plasma. of formation f o of the activve form  Small quantities of h heparin can n of vitamin v K → ↓ synthes sis of Mechanism of action activate anntithrombin n III leading vita amin K-dep pendent cllotting to inhibitio on of severral clotting factors (II, VIII, IX, and X). X factors especially fac ctor X &  Thee action off warfarin could c thrombin (factor ( II). be antagonizeed by vitam min K. Onset and Immediate and a short ((2-4 hrs). Delayyed for 8-1 2 hrs (time e duratio on needeed for deple letion of clo otting factorrs & vit K) aand long (33-7 d) Pharma acol  Anticoagullant in vivo o & in vitro Antico oagulant in n vivo only y. effects s  Stimulates s lipoproteiin lipase → ↓↓ serum triglyceride t es (TGs). Therappeu-  Treatmennt of estabblished Warfa arin is givenn oral 2-10 0 tic use es thrombos sis: heparin n is given mg/daay for prevvention an nd parenteral 5000-10,0000 U i.v. treatm ment of: then 5000 U s.c./8h to maintaiin – Deeep vein thrrombosis (DVT) ( blood coagulation 2--3 times ass – Posstoperativee thrombossis. normal and preventt further – Cerrebral venoous thromb bosis. 209  extension of the thrombus. – Coronary thrombosis: treatment continued for  Prevention of thrombosis: several years. 5000 U s.c./8-12 hrs. – Acute arterial & pulmonary embolism: anticoagulation is initiated by heparin and maintained by warfarin. – AF and artificial heart valves Monitor- By activated partial thrombo- By prothrombin time (PT) or ing of plastin time (APTT). International Normalized Ratio therapy It must be kept 2-3 times as the (INR). It is the ratio of the PT in normal value. the patient to that of normal person. It must be kept 2-3 times as the normal value. Adverse  Bleeding is the most common and dangerous SE (e.g. hematuria effects & major organ bleeding). It could be treated by the following: (a) Immediate stopping of the drug. (b) Fresh frozen plasma (FFP): to provide fresh clotting factors. (c) Protamine sulfate (Protam): (c) Vitamin K1: 10 mg slowly - Protamine carries +ve charge i.v. or i.m. to enhance that combines with heparin synthesis of clotting factors. (carries -ve charge) to form stable complex. - 1 mg of protamine can bind to 100 U of heparin.  Hematoma if given IM (so, con-  Hemorrhagic skin necrosis: traindicated to give it IM). when starting warfarin, biosyn-  Thrombocytopenia: immune- thesis of protein C is reduced mediated reaction due to for- leading to temporary procoag- mation of antibodies that can ulant state. This can lead to bind to platelets. Platelet count hemorrhagic infarction of skin, should be performed regularly breast, intestine and fatty tiss-  Osteoporosis and spontaneous ue. normally avoided by conc- fractures on long-term therapy urent heparin administration.  Alopecia and dermatitis: rare  Teratogenicity: abnormal bone and transient. formation in early pregnancy (fetal warfarin syndrome).  CNS Hemorrhage in the fetus if given in late pregnancy.  Sudden withdrawal may lead to thrombotic catastrophes. 210 Low-m moleculaar-weigh ht hepari ns (LMW WH) (Enoxa aparin – Dalteparin) D )  Sta nfractionatted) heparrin is a andard (un mixxture of different d molecular m weight frac ctions (MW W 3000-30,000 Da) thhat can affe ect more th han one cooagulation n factor andd produce thromboc cytopenia (↑ risk of b bleeding).  LMW WH has a MW less than 80 000 Da thatt makes it specific for f factor X with minnimal effec cts on platelets and d other clottting factorrs. Unfra actionated d heparin LMWH H Molecu ular weightt range Wide (ranges fro om 3000 to o Less thhan 8000 Da D 30,00 00 Da) Anti-fac ctor Xa acttivity Less sspecific More sspecific Non-sppecific bind ding to High Low vascula ar endothe elium and plasma a proteins Bioavailability after s.c. Low High injectio on (due tto binding to s.c. tissue) e) Half-life e Short (given 3 tiimes/d) Long (g given once e/d) Thromb bocytopen nia Comm mon (10%)) Less ccommon (<