Drug used in disorders of coagulation

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Drug used in disorders of coagulation

• Vladimír Moravec, M.D.

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Mechanisms of blood coagulation

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

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Blood coagulation

• Two pathways
• 1.Intrinsic system
• 2.Extrinsic system
• Viz.Figure

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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)

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Bleeding therapy

• Haemostatics - local vasoconstriction
• Antifibrinolytics - inhibit fibrinolysis
• Antiaggregants against platelets agregation
• Fibrinolytics rapidly lyse thrombus
• Anticoagulants -?blood coagulation

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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.

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Somatostatin

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

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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

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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.

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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.

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2. Pharmacology of the anticoagulant drugs

• 1.- Heparin X Protamin sulfat, Antitrombin III.,
  LMWH,
• Fraxiparin
• 2. - Warfarin X Vit K, Pelentan
• Dicumarol, Phenprocoumon (6days)

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

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

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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.

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LMWH

• Generic name antiXa/IIa t 1/2
  (hod)
• Dalteparin 2 1
  119-139
• sodium
• Nadroparin 3,2 1
  132-162
• calcium
• Enoxaparin 2,7 1
  129-180
• sodium
• Tinzaparin 1,9 1
  111
• sodium

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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

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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

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3. Fibrinolytic drugs

• Rapidly lyse thrombi by catalyzing plasmin
  protease from its precursor plasminogen.
• Fibrin degradation
• Administered by intravenous infusion
• (250 000 units, followed by 100 000 units/h
• Indication multiple pulmonary emboli, central
  deep venous thrombosis, acute myocardial
  infarction
• Viz figure

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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.

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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.

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FIBRINOLYTICS
FIBRINOLYTICS
Plasminogen
Inhibition
Activation
Various stimuli

Blood proactivator
Blood activator
-

Antiactivators
urokinase
-

Streptokinase
Activator

Proactivator
Plasmin
t-PA
Anistreplase


Thrombin
Fibrin split products
Degradation products
Fibrinogen
Fibrin
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Antifibrinolytics

• Antidotum Aprothinin, PAMBA, Etha aminokapronic
  acid.

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

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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

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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?? 100-325 mg/day

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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.

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Ticlopidin a Clopidogrel
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Ticlopidin - negatives??

• Adverse ractions
• Granulocytopenie
• ( 2,4 cases).
• Ticlopidin is more
• Expensive against aspirin.

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Abciximab

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

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5. Drugs used in bleeding disorders

• Vitamin K
• Fibrinogen
• Deficience of f. VIII., f. IX.
• Fibrinolytic inhibitors
• Aminocapronic acid, PAMBA, Aprothinin

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Thank you...