1. Drug used in disorders of coagulation
Vladimír Moravec, M.D.

2. Mechanisms of blood coagulation
Trombogenesis:
the platelet - white trombus - red trombus
Hemostasis:
1.adhesion and activation of platelets
2.fibrin formation
3.vascular contraction

4. Blood coagulation 1.Intrinsic system 2.Extrinsic system Two pathways:
Viz.Figure

6. Monitoring of coagulation
1. Extrinsic koagulo-pathways - components presents in plasma – aPTT
2. Intrinsic koagulo-pathways – with participation of tishue components –
Prothrombin time (Quick test),
INR (International normalized ratio)

7. Bleeding therapy Haemostatics - local vasoconstriction
Antifibrinolytics - inhibit fibrinolysis
Antiaggregants – against platelets agregation
Fibrinolytics – rapidly lyse thrombus
Anticoagulants -blood coagulation

8. 1. Haemostatic drugs Somatostatin Antithrombin III
Protamine sulfate, vitamin K - antidotum
Ethamsylate - facility of platelets agregation
Desmopressin, Terlipressin
Vasopresin, alfamimetics – vasoconstriction
Global efficacy : plasma, coagul. factors
Local efficacy: gelatin, collagen
Deficience of factors F. VIII., F. IX.

9. Somatostatin
naturally occurring tetradecapeptide that produces numerous physiologic effects.
rapidly inactivated by peptidase enzymes; its plasma half-life is 1 to 3 minutes.

10. Clinical applications
efficacy in a variety of clinical conditions, including carcinoid syndrome, enterocutaneous and pancreatic fistulas, the dumping syndrome, VIPomas, glucagonomas, diabetes mellitus, insulin excess in neonates, psoriasis, and short-bowel syndrome
its efficacy in upper gastrointestinal bleeding is controversial

11. ANTITHROMBIN III
purified preparations of antithrombin III derived from human plasma.
Antithrombin III concentrate is primarily used for the prophylaxis and treatment of patients with congenital antithrombin III deficiency and disseminative intravascular coagulopathy.

12. PROTAMINE SULFAT
strongly basic protein that is capable of neutralizing the effects of HEPARIN.
dose is 1 mg IV for every 100 units of HEPARIN remaining in the patient; doses of 50 mg should not be exceeded within a 10-minute period to decrease the risk of adverse effects; the dose is usually administered by intravenous bolus over 1 to 3 minutes, but a constant infusion over 30 minutes may also be given.

13. 2. Pharmacology of the anticoagulant drugs
1.- Heparin X Protamin sulfat, Antitrombin III., LMWH,
Fraxiparin
2. - Warfarin X Vit K, Pelentan
Dicumarol, Phenprocoumon (6days)

14. ANTICOAGULANTS
1. direct - Heparin (antidotum-Protamin sulfat), Antithrombin III., Low-molecula-weight-heparin(LMWH) , Heparinoids – (local)

15. 2. indirect - Warfarin (antidotum Vit K), Pelentan
ANTICOAGULANTS
2. indirect - Warfarin (antidotum Vit K), Pelentan

16. Heparin aktivation Antithrombin III.
Inhibition of thrombocyt agregation
Aktivation of lipoprotein lipase (hypolipidemic effect)
bolus 5-10 tis. m.j., 1 tis. J/hod, aPTT
Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT)
In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin.

19. Generic name: antiXa/IIa t 1/2 (hod)
LMWH
Generic name: antiXa/IIa t 1/2 (hod)
Dalteparin :
sodium
Nadroparin ,2 :
calcium
Enoxaparin ,7 :
Tinzaparin ,9 :

20. Hirudin In nature - Hirudo medicinalis
Specific thrombin inhibitor from the leech.
Now is prepared by recombinant DNA technology – lepirudin
selective inhibitor of thrombinu,
action is independent of ATIII.
Hirudin has litle effect on platelets or the bleeding time.
APTT monitoring
antidotum is not available

21. Cumarine anticoagulants
Oral anticoagulants.
Block the carboxylation of several glutamate residues in prothrombin and factors VII, IX, X., and protein C.(endogenous anticoagulans)
antagonists of Vitamin K - f. VII, IX, X,
dicumarol - Etylbiskumacetate (Pelentan)
monocumarin - Warfarin , 1xd

22. 3. Fibrinolytic drugs
Rapidly lyse thrombi by catalyzing plasmin protease from its precursor plasminogen.
Fibrin degradation
Administered by intravenous infusion
( units, followed by units/h
Indication: multiple pulmonary emboli, central deep venous thrombosis, acute myocardial infarction
Viz figure

24. Fibrinolytics drugs trombolytics 1. generation :
streptokinase, urokinase – not selective, systemic fybrinolysis
trombolytics 2. generation:
tissue plasminogen activators (tPA)
with recombinant types: rt-PA
Alteplase - is unmodified human t-PA.
Antistreplase (ASPAC)- anisolated plasminogen streptokinase activator complex.

25. Fibrinolytics drugs
Streptokinase is a protein synthetised by streptococci that combines with the plasminogen. This complex catalyzes the conversion of inactive plasminogen to active plasmin.
Urokinase is a human enzyme synth. By the kidney that directly converts to plasmin.
Antistreplase consists of a complex plasminogen and streptokinase that has been acylated to protect.

26. FIBRINOLYTICS FIBRINOLYTICS Plasminogen Inhibition Activation
Various stimuli +
Blood
proactivator
Blood
activator + -
Antiactivators
urokinase + -
Streptokinase
Activator +
Proactivator
Plasmin
t-PA
Anistreplase + +
Thrombin
Degradation
products
Fibrin split
products
Fibrinogen
Fibrin

28. Antifibrinolytics
Antidotum: Aprothinin, PAMBA, Etha aminokapronic acid.

30. 4. Antitrombotic drugs:
Drug that antagonize pathway interfere with platelet agregation in vitro and prolong the bleeding time in vivo.

31. Platelet function is regulated
Platelet function is regulated by three categories of substances:
Contains agents generated within the platelet that interact with membrane receptors:
Catecholamines, collagen, thrombin, prostacyclin
ADP, prostaglandinD2, E2, serotonin
Paltelets within platelet: cAMP a cGMP, TxA2

32. Antitrombotic - antiplatelet drugs
Representants:
Aspirin – inhibition of prostaglandine meetabolisme
Ticlopidin, Clopidogrel – inhibition of ADP-induced platelet aggregation
Dipyridamol
Abciximab – parenteral – blockade of GP 2b/3a

35. Aspirin, ASA
Aspirin inhibits the synthesis of TxA by irreversible acetylation of the enzyme cyclooxygenase 2. The platelet canot manufacture new enzyme during its 10-day lifetime.
Prolong the bleeding time.
Studies were conducted to ëwaluate the use of aspirin for 4-5 years in the primary profylaxis of cardiovascular mortality.
Dosses?? mg/day

36. Ticlopidine
Reduce platelet aggregation by inhibiting the ADP pathways of platelets.
Adverse effects include nausea, dyspepsia, hemorage, leukopenia.
Dosage is 250 mg/twice day
Its useful in patients who cannot tolerate aspirin.

37. Ticlopidin a Clopidogrel

38. Ticlopidin - negatives??
Adverse ractions:
Granulocytopenie
( 2,4% cases).
Ticlopidin is more
Expensive against aspirin.

39. Abciximab
New class of platelet-inhibiting drug that blocks platelet receptors.
Is a mouse/human chimeric monoclonal antibody that blocks IIb/ IIIa receptors.

40. 5. Drugs used in bleeding disorders
Vitamin K
Fibrinogen
Deficience of f. VIII., f. IX.
Fibrinolytic inhibitors:
Aminocapronic acid, PAMBA, Aprothinin

41. Thank you...