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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