drug used in disorders of coagulation vladimír moravec, m.d
TRANSCRIPT
Drug used in disorders of coagulation
Vladimír Moravec, M.D.
Mechanisms of blood coagulation
Trombogenesis:the platelet - white trombus - red
trombus
Hemostasis:1.adhesion and activation of platelets2.fibrin formation3.vascular contraction
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The Coagulation Cascade
Central to the coagulation cascade is the generation of thrombin (factor IIa)
thrombin is generated from prothrombin by the action of activated factor X (Xa)
thrombin then acts on fibrinogen to generate fibrin clot
Blood coagulation
Two pathways:1.Intrinsic system2.Extrinsic system
Viz.Figure
The in vivo pathway(extrinsic pathway)
The in vitro contact system(intrinsic pathway)
Contact(e.g. with endoth)
XIIa XII
XIa XI
IXa IX
X Xa
Tissue damage
Fibrinogen Fibrin Stabilised fibrin
II (Prothrombin IIa (Thrombin)
VIIIa, PL, Ca2+
Va, PL, Ca2+ +
+
XIII Ca2+
XIIIa
Platelets
+
Tissue factorVIIaPLCa2+
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)
Bleeding therapy
1. Haemostatics - local vasoconstriction2. Antifibrinolytics - inhibit fibrinolysis3. Antiaggregants – against platelets
agregation4. Fibrinolytics – rapidly lyse thrombus5. Anticoagulants -blood coagulation
1. Haemostatic drugsSomatostatin 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.
Somatostatin
naturally occurring tetradecapeptide that produces numerous physiologic effects.
rapidly inactivated by peptidase enzymes; its plasma half-life is 1 to 3 minutes.
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
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.
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.
2. Pharmacology of the anticoagulant drugs
1.- Heparin X Protamin sulfat, Antitrombin III., LMWH,
Fraxiparin
2. - Warfarin X Vit K, PelentanDicumarol, Phenprocoumon
(6days)
ANTICOAGULANTS
H2COSO3-
O
65
4
3 2
1
O
NHCOCH3(nebo –SO3
-)
OH O OH
COO-
OH
O O OO
O
(or –H)H2COSO3
-
OSO3-
NHSO3-
O
COO-
OH
OSO3-
H2COSO3-
OH
NHSO3-
OO
N-acetyl glucosamin kyselina glukuronová N-sulfonovaný kyselina iduronová N-sulfonovaný6-O-sulfát glukozamin (2-O-sulfát) glukozamin
3,6-O-disulfát (6-O-sulfát)
Heparin chain with binding place for ATIII
1. direct - Heparin (antidotum-Protamin sulfat), Antithrombin III., Low-molecula-weight-heparin(LMWH) , Heparinoids –
(local)
ANTICOAGULANTS
O
R
CH3
O
O
CHCH2COCH2
O
ONa C6H5
Vitamin K Warfarin(vit.K antagonist)
Chemical strukture: vit. K and warfarinu
2. indirect - Warfarin (antidotum Vit K), Pelentan
Heparin
aktivation Antithrombin III. Inhibition of thrombocyt agregationAktivation 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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Low-molecular-weight heparin
UH (mw 3k - 30k) is a heterogeneous mixture of polysacchride chains (glycosaminoglycans)
LMWH (mw 5k) is obtained by alkaline degradation of heparin benzyl ester
LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio
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Mechanism of Action
Both UH and LMWH exert their anticoagulation activity by catalyzing antithrombin (AT or AT III)
catalyzed AT is accelerated in its inactivation of the coagulation enzymes thrombin (factor IIa) and factor Xa.
prolongs aPTT
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
Hirudin
In nature - Hirudo medicinalisSpecific 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
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
3. Fibrinolytic drugs
Rapidly lyse thrombi by catalyzing plasmin protease from its precursor plasminogen.
Fibrin degradationAdministered 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
Plasminogen
Plasmin
Degradationproducts
Fibrinogen Fibrin Fibrin splitproducts
Activation Inhibition
Various stimuli+
+Blood
proactivatorBlood
activator
+
+ Activator
-
-
+ +
Thrombin
Antiactivators
Fibrinolysis
t-PA
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.
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.
Plasminogen
Plasmin
Degradationproducts
Fibrinogen FibrinFibrin splitproducts
Activation Inhibition
Various stimuli+
+Blood
proactivatorBlood
activator
+ urokinase
+ActivatorStreptokinase
Proactivator
Anistreplase
-
-
+ +
Thrombin
Antiactivators
FIBRINOLYTICSFIBRINOLYTICS
t-PA
Antifibrinolytics
Antidotum: Aprothinin, PAMBA, Etha aminokapronic acid.
Plasminogen
Plasmin
Degradationproducts
Fibrinogen Fibrin Fibrin splitproducts
Activation Inhibition
Various stimuli+
+Blood
proactivatorBlood
activator
+ T-PA
-
-
+ +
Thrombin
aminocaproic acid
ANTIFIBRINOLYTICS
aprotinin-
Activator
4. Antitrombotic drugs:
Drug that antagonize pathway interfere with platelet agregation in vitro and prolong the
bleeding time in vivo.
Platelet function is regulated
Platelet function is regulated by three categories of substances:
Contains agents generated within the platelet that interact with membrane receptors:
1. Catecholamines, collagen, thrombin, prostacyclin
2. ADP, prostaglandinD2, E2, serotonin3. Paltelets within platelet: cAMP a cGMP,
TxA2
Antitrombotic - antiplatelet drugs
Representants:Aspirin – inhibition of prostaglandine meetabolisme
Ticlopidin, Clopidogrel – inhibition of ADP-induced platelet aggregation
DipyridamolAbciximab – parenteral – blockade of GP
2b/3a
KolagenTrombin
TXA2
Aspirin
(FibrinogenReceptor)
(FibrinogenReceptor)
ADP = adenosine difosfát, TXA2 = tromboxan A2, COX = cyklooxygenása.Schafer AI. Am J Med. 1996;101:199–209.ADP = adenosine difosfát, TXA2 = tromboxan A2, COX = cyklooxygenása.Schafer AI. Am J Med. 1996;101:199–209.
clopidogrel
TXA2
ADP
DipyridamolDipyridamol
ProstacyclinProstacyclinADP
Gp IIb/IIIaGp IIb/IIIa Aktivace
COX
ticlopidine
IIb/IIIa antagonists
Effect of antiplatelet drugs:
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
Ticlopidine
Reduce platelet aggregation by inhibiting the ADP pathways of platelets.
Adverse effects include nausea, dyspepsia, hemorage, leukopenia.
Dosage is 250 mg/twice dayIts useful in patients who cannot
tolerate aspirin.
Ticlopidin a Clopidogrel
Ticlopidin - negatives??
Adverse ractions: Granulocytopenie ( 2,4% cases).
Ticlopidin is more Expensive against aspirin.
Abciximab
New class of platelet-inhibiting drug that blocks platelet receptors.
Is a mouse/human chimeric monoclonal antibody that blocks IIb/ IIIa receptors.
5. Drugs used in bleeding disorders
Vitamin K
FibrinogenDeficience of f. VIII., f. IX.Fibrinolytic inhibitors:Aminocapronic acid, PAMBA,
Aprothinin
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