Transcript Bez nadpisu - Univerzita Karlova v Praze

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 platelets
2.fibrin formation
3.vascular contraction
Blood coagulation
Two pathways:
1.Intrinsic system
2.Extrinsic system
Viz.Figure
The in vitro contact system
(intrinsic pathway)
The in vivo pathway
(extrinsic pathway)
Contact
Tissue damage
(e.g. with endoth)
Tissue factor
VIIa
PL
Ca2+
XIIa
XIa
IXa
XI
Platelets
IX
VIIIa, PL, Ca2+
X
+
+
Xa
Va, PL, Ca2+
II (Prothrombin
XII
+
XIII
Ca2+
IIa (Thrombin)
XIIIa
Fibrinogen
Fibrin
Stabilised fibrin
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 vasoconstriction
2. Antifibrinolytics - inhibit
fibrinolysis
3. Antiaggregants – against platelets
agregation
4. Fibrinolytics – rapidly lyse thrombus
5. Anticoagulants -blood coagulation
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.
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 shortbowel 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, Pelentan
Dicumarol, Phenprocoumon (6days)
ANTICOAGULANTS
Heparin chain with binding place for
ATIII
H2COSO3 6
5
O
O
4
O
1
OH
3
(or –H)
H2COSO3 -
COO-
2
COO-
O
OSO3-
OH
OH
kyselina glukuronová
O
O
O
O
NHCOCH3
(nebo –SO3-)
N-acetyl glucosamin
6-O-sulfát
H2COSO3 O
O
NHSO 3-
N-sulfonovaný
glukozamin
3,6-O-disulfát
OH
OSO3-
kyselina iduronová
(2-O-sulfát)
OH
O
NHSO 3-
N-sulfonovaný
glukozamin
(6-O-sulfát)
1. direct - Heparin (antidotum-Protamin sulfat),
Antithrombin III., Low-molecula-weightheparin(LMWH) , Heparinoids – (local)
ANTICOAGULANTS
2. indirect - Warfarin (antidotum Vit K),
Pelentan
Chemical strukture: vit. K and warfarinu
ONa
O
R
CH3
C6H5
CHCH2COCH2
O
O
O
Vitamin K
Warfarin
(vit.K antagonist)
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.
LMWH
Generic name:
Dalteparin
antiXa/IIa
2:1
t 1/2 (hod)
119-139
sodium
Nadroparin
Enoxaparin
3,2 : 1
calcium
2,7 : 1
132-162
129-180
sodium
Tinzaparin
1,9 : 1
sodium
111
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
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 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
Fibrinolysis
Plasminogen
Activation
Various stimuli
+
Blood
Blood
+
proactivator
activator
+
t-PA
Inhibition
Antiactivators
-
Activator +
Plasmin
+
Degradation
products
+
Thrombin
Fibrinogen
Fibrin
Fibrin split
products
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.
FIBRINOLYTICS
Plasminogen
Activation
Various stimuli
+
Blood
Blood
+
proactivator
activator
urokinase +
-
Inhibition
Antiactivators
-
Streptokinase
Activator
Proactivator
t-PA Anistreplase
Degradation
products
+
Plasmin
+
+
Thrombin
Fibrinogen
Fibrin
Fibrin split
products
Antifibrinolytics
Antidotum: Aprothinin, PAMBA, Etha
aminokapronic acid.

ANTIFIBRINOLYTICS
Plasminogen
Activation
Various stimuli
+
Blood
Blood
+
proactivator
activator
-
T-PA
Activator
Inhibition
aminocaproic acid
+
-
Plasmin
+
Degradation
products
aprotinin
+
Thrombin
Fibrinogen
Fibrin
Fibrin split
products
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, serotonin
3. Paltelets within platelet: cAMP a cGMP, TxA2
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
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 day
Its 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
Fibrinogen
Deficience of f. VIII., f. IX.
Fibrinolytic inhibitors:
Aminocapronic acid, PAMBA, Aprothinin
Thank you...