Bez nadpisu

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DRUGS USED IN DISORDERS OF HEMOSTASIS prof.
MUDr. Jirina Martínková,CSc. 2008
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INTRODUCTION

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Hemostasis is the spontaneous arrest of bleeding
from a damaged blood vessel
phase of vasoconstriction (TXA2, 5-HT)
platelet phase platelet adhesion - platelet
aggregation (ADP, TXA2)- viscous metamorphosis
- a platelet plug - a white thrombus
(initially forms in high-pressure arteries)
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phase of coagulation (local production of
thrombin) the platelet plug is reinforced by
fibrin for long-term effectiveness a
red thrombus (around a white thrombus or de novo
in low-pressure veins)
PGI2 (vasodilation, inhibition of aggregation)
- fibrinolysis - inhibitors of activated
clotting factors-ATIII, protein C and S
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platelet phase
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Receptors of platelets and their agonists
Gp Ib f.V, fVIII
Gp IIb/ IIIa fibrinogen
ADP
COX1
TXA2
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phase of coagulation
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The in vitro contact system (intrinsic pathway)
The in vivo pathway (extrinsic pathway)
Contact (e.g. with glass)
Tissue damage
Tissue factor VIIa PL Ca2
XIIa XII
XIa XI
Platelets
IXa IX
VIIIa, PL, Ca2

X Xa

XIII Ca2 XIIIa
Va, PL, Ca2

II (Prothrombin) IIa
(Thrombin)
Fibrinogen Fibrin Stabilised
fibrin
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At each step, a clotting factor undergoes limited
proteolysis and becomes an active protease. This
protease activates the next clotting factor,
untill finally a solid fibrin clot is formed.
Both coagulation and fibrin formation must be
confined to a smaller possible area to achieve
local hemostasis in response to bleeding from
injury without causing disseminated coagulation
of impaired blood flow. Two systems to reach
it - plasma contains protease inhibitors that
rapidly inactivate the coagulation proteins as
they escape from the site of vessel injury
ATIII, protein C and S, alpha2 antiplasmin, -
fibrinolysis The central process is conversion of
inactive plasminogen to the proteolytic enzyme
plasmin. Plasmin limits the extension of thrombus
by proteolytic digestion of fibrin.
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fibrinolysis
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-
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ALTERED STATES OF HEMOSTASIS thrombosis bleedi
ng
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Thrombosis is the pathological formation of a
hemostatic plug resulting from inappropriate
activation of hemostatic mechanisms. Drug therapy
to treat or prevent thrombosis is extensively
used because such diseases are common as well as
serious Aa white thrombus ---- a local
occlusive ischaemia a red thrombus -----
deep vein thrombosis and distent embolism The
main drugs used for platelet-rich white thrombi
ANTIPLATELET DRUGS
FIBRINOLYTIC DRUGS The main drugs used to treat
red thrombus ANTICOAGULANTS

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DRUGS USED IN DISORDERS
OF HEMOSTASIS I. Drugs reducing processes
of hemostasis ANTIPLATELED AGENTS
ANTICOAGULANT DRUGS
(antithrombotics) FIBRINOLYTICS
(thrombolytics) II. Drugs used in bleeding
disorders HEMOSTATICS
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DRUGS USED IN DISORDERS
OF HEMOSTASIS I. Drugs reducing processes
of hemostasis ANTIPLATELED AGENTS
ANTICOAGULANT DRUGS FIBRINOLYTICS
II. Drugs used in bleeding disorders
HEMOSTATICS
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I. Drugs reducing processes of hemostasis
platelet phase ANTIPLATELET AGENTS
reduce platelet aggregation Aspirin inhibits
the synthesis of thromboxane A2 by irreversible
acetylation of the enzyme cyclooxygenase
(COX-1) in doses appr. 325 mg/day. The effects
last for 7-10 days (bleeding!) Ind. primary
prophylaxis of myocardial infarction
secondary prevention of vascular
events Clopidogrel and ticlopidin inhibit the
ADP pathway of platelet aggregation Ind.
prevention of thrombosis in patients undergoing
placement of a coronary stent
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Receptors of platelets, agonists and antagonists
Gp Ib ( f. V / VIII)
Gp IIb/ IIIa fibrinogen abciximab
COX1
ADP dipyridamol ticlopidine clopidogrel
Aspirin
TXA2
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• Drugs reducing processes of hemostasis
• platelet phase ANTIPLATELET AGENTS

Abciximab (a humanized monoclonal antibody)
directed against the IIb/IIIa receptors
located at the surface of thrombocytes
(necessary for platelet aggregation) A.
produces their blockade inhibits
platelet aggregation Ind acute coronary
syndrome
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DRUGS USED IN DISORDERS
OF HEMOSTASIS I. Drugs reducing processes
of hemostasis ANTIPLATELED AGENTS
ANTICOAGULANT DRUGS FIBRINOLYTICS
II. Drugs used in bleeding disorders
HEMOSTATICS
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I. Drugs reducing processes of hemostasis
in phase of coagulation ANTICOAGULANT
DRUGS IN -VITRO
IN- VIVO
IN- VIVO IN-VITRO ANTICOAGULANT DRUGS
IN -VITRO Sodium citrate,
EDTA bind Ca Use prevention
of blood coagulation in laboratory methods

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The in vitro contact system (intrinsic pathway)
The in vivo pathway (extrinsic pathway)
Contact (e.g. with endoth)
Tissue damage
Tissue factor VIIa PL Ca2
XIIa XII
XIa XI
Platelets
IXa IX
VIIIa, PL, Ca2

X Xa

XIII Ca2 XIIIa
Va, PL, Ca2

II (Prothrombin IIa
(Thrombin)
Fibrinogen Fibrin Stabilised
fibrin
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I. Drugs reducing processes of hemostasis-
warfarin
ANTICOAGULANT DRUGS
IN -VIVO (oral anticoagulants)
block the ?-carboxylation of several
glutamate residues in prothrombin (f II)
and factors VII, IX and X as well as the
endogenous anticoagulant proteins C and S The
blockade results in incomplete molecules that are
biologically inactive in coagulation
bishydroxycoumarin (formed in spoiled sweet
clover) its congener warfarin
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The in vitro contact system (intrinsic pathway)
The in vivo pathway (extrinsic pathway)
Contact (e.g. with glass)
Tissue damage
Tissue factor VIIa PL Ca2
XIIa XII
XIa XI
Platelets
IXa IX
VIIIa, PL, Ca2

X Xa

XIII Ca2 XIIIa
Va, PL, Ca2

II (Prothrombin IIa
(Thrombin)
Fibrinogen Fibrin Stabilised
fibrin
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I. Drugs reducing processes of hemostasis-
warfarin
Warfarin
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I. Drugs reducing processes of hemostasis-
warfarin
pharmacodynamics onset of action depends on
absorption on a balance
between partially inhibited synthesis and
unaltered degradation of the 4 vitamin
K-dependent clotting factors t 1/2 f
VIIa 6 h f IXa, Xa, IIa -----
24, 40 and 60 h resp. there is an
8 to 12-hour delay in the action of warfarin Cmax
in 1 h while the maximum effect is reached at
48 h. The effect lasts for 4-5
days pharmacokinetics well absorbed, binds to
plasma proteins ( gt90), eliminated via CYP 450,
crosses the placenta (pregnancy!) w. does not
appear in breast milk

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I. Drugs reducing processes of hemostasis-
warfarin

• interindividual and intraindividual variability
  in response
• Factors modifying the effects of warfarin
• impairment of hepatic function (decrease in
  biosynthesis of
• clotting factors)
• inhibition of w. elimination due to CYP 450
  blockade
• (amiodarone, clarithromycin)
• competition for binding sites of plasma
  proteins (NSAID)
• decrease in production of vit K (antibiotics
  with broad spectrum)
• intake of vit. K (incl. food - broccoli)
• enzymatic induction of CYP 450 (carbamazepine,
  barbiturates)

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I. Drugs reducing processes of hemostasis-
warfarin
Monitoring warfarin therapy prothrombin timeINR
(International Normalized Ratio)
prothrombin time ratio (test/control) obtained
if the more sensitive international reference
thromboplastin made from human brain is
used. Current guidelines recommend INR level of
2.0-3.0 Dosage how much? how long? Treatment
with warfarin should be initiated with daily
doses of 5-10 mg. The initial adjustment of the
prothrombin time results in a maintained dose of
3-7 mg/day. Duration of w. therapy depends on
whether risk factors continue (i.e. inherited
disorders, prolonged immobilization). If no
continuing factors are identified, a 3-month
course of w.therapy can be appropriate.
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I. Drugs reducing processes of hemostasis
-warfarin

• Unwanted effects
• bleeding
• can be reversed by stopping the drug
• administering
  large doses of vitamin K1 (i.v)
• in emergency fresh-frozen plasma orclotting
  factors concentrates
• skin necrosis -hemorrhagic infarction- after the
  start of therapy with warfarin in patients with
  deficiency of protein C.
• The pathological lesion associated with
• the hemorrhagic
  infarction is venous thrombosis.
• teratogenic action - during pregnancy w. can
  cause
• - a serious defect characterized by
  abnormal bone
• formation, central
  nervous system abnormalities
• - a hemorrhagic disorder in the
  fetus
• warfarin is contraindicated during
  pregnancy

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I. Drugs reducing processes of hemostasis -
warfarin

• Contraindications
• bleeding
• severe hypertension
• danger of bleeding (cancer, ulcers in the GIT,
  surgery)
• severe hepatic and/or renal impairment
• pregnancy
• Ind
• venous thromboembolism. The long-term
  prophylaxis against new
• or recurrent DVTs and pulmonary embolism
• myocardial infarction. W. can prevent
  reocclusion,
• thromboembolic phenomena associated with
  atrial fibrillation
• stroke
• mechanical heart-valve replacement

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I. Drugs reducing processes of hemostasis
ANTICOAGULANT DRUGS
IN-VIVO IN -VITRO heparin is a
heterogenous mixture of sulfated
mucoolysaccharides, widely distributed on a
variety of normal tissue (mastocytes).
unfractionated (UFH) MW 5 000-40 000 d
LMWH MW lt5 000
d UFH is commercially obtained from either bovine
lung or porcine intestinal mucosa As a
result, the anticoagulant activity is variable
because the chain length of the molecules affects
activity and clearance of heparin.
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Heparin pentasaccharide
(or H) H2COSO3-
H2COSO3-
COO-
H2COSO3-
6
O
5
O
O
O
O
COO-
4
1
O
O
O
OH
OH
OH
O
OSO3-
OH
O
O
3
2
NHSO3-
OH
NHSO3-
NHCOCH3 (orSO3-)
OSO3-
iduA
GlcN
The antithrombin binding region of commercial
heparin consists of repeating sulfated
disaccharide units composed of D-glucosamine
(GlcN)- L-iduronic acid (iduA)
and D-glucosamine-D-glucuronic
acid
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I. Drugs reducing processes of hemostasis- heparin

• Pharmacodynamics
• the anticoagulant action of H. is mediated
  through its ability to bind to ATIII and
  accelerate its anticoagulant activity
  (1000-fold).
• AT III is a member of the serine protease
  inhibitor family which regulates coagulation by
  inactivating some activated clotting factors
  (coagulation proteases) by irreversible complex
  formation IIa, Xa, f IXa, XIa, XIIa
• H. also interferes with clotting factors on
  the platelet surface
  
• ---
  inhibition of platelet aggregation
• Pharmacokinetics
• UFH is a highly charged molecule --- is poorly
  transported across biological membranes
  administration i.v. (immediate effects), s.c.
  (effect in 1-2 h), maximum effect in 3 h,
  duration 12-18 h.

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The in vitro contact system (intrinsic pathway)
The in vivo pathway (extrinsic pathway)
Contact (e.g. with glass)
Tissue damage
Tissue factor VIIa PL Ca2
XIIa XII
XIa XI
Platelets
IXa IX
VIIIa, PL, Ca2

X Xa

XIII Ca2 XIIIa
Va, PL, Ca2

II (Prothrombin IIa
(Thrombin)
Fibrinogen Fibrin Stabilised
fibrin
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I. Drugs reducing processes of hemostasis -
heparin
T 1/2 60-90 min UFH does not cross the
placenta, does not appear in breast
milk Monitoring heparin therapy APTT Unwanted
effects bleeding protamin sulfate
for every 100 IU of heparin remaining in the
patient / 1 mg of PS i.v. thrombocytopenia-
transient form in 25
severe form in 5 (mortality 30) antibody
mediated cause that is associated with
thrombosis. The heparin-induced antibody is
directed against the heparin-platelet factor 4
complex. These complexes bind to receptors on
adjacent platelets, causing aggregation and
paradoxical thromboembolism.
administ. of an alternative drugs -- hirudin
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I. Drugs reducing processes of hemostasis -
heparin

• Unwanted effects to be continued
• osteoporosis (duration of therapy with heparin gt
  6 months)
• dosage
• an initial dose of heparin is chosen, and
  subsequent dosage adjustment are guided by APTT
  assays.
• For example it is recommended that patients
  with proximal DVT should be given a bolus loading
  dose of 5000 IU i.v. followed by a continuous
  infusion (20 to 25 IU/kg per hour).
• The goal is to rapidly achieve prolongation of
  the APTT between 2 and 4 times the laboratory
  control APTT.

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I. Drugs reducing processes of hemostasis -
heparin

• Contraindications
• hypersensitivity
• patients actively bleeding
• hemophilia, thrombocytopenia, purpura
• severe hypertension
• intracranial hemorrhage
• ulcerative lesions of the GIT , visceral
  carcinoma,
• advanced hepatic or renal disease
• despite of the apparent lack of placental
  transfer,
• heparin should be used in pregnant women only
  when
• clearly indicated

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I. Drugs reducing processes of hemostasis - LMWHs

• LMWHs
• pharmacodynamics
• inhibit f Xa but have less effect on AT III and
  on coagulation in general
• generic name antiXa/IIa
  t 1/2 h
• dalteparin 21
  119-130
• enoxaparin 2.7 1
  129-180
• nadroparin 3.2 1
  132-162
• s.c., once or twice daily, the effect is
  correlated with the dose/b.w.
• no need for therapy monitoring except
  for renal failure (anti Xa activity measuring is
  recommended)
• Less danger of unwanted effects

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ACTION of UH and LMWH
UH - unfractionated heparin ATIII -
antithrombin III LMWH - low molecular weight
heparin
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I. Drugs reducing processes of hemostasis -
hirudin
Hirudin powerful and selective fIIa
(thrombin) inhibitor from the leech (Hirudo
medicinalis) independent of ATIII which is
available in recombinant form as lepirudin
Monitoring by APTT, no antidote exists
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I. Drugs reducing processes of hemostasis -
hirudin
n e w a p p r o a c h e s
anticoagulants with selective inhibition of
the target molecule
fIIa and fXa The goal . rapid onset of
action . shorter action without
monitoring . oral
administration
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I. Drugs reducing processes of hemostasis -
hirudin
- Indirect inhibitors of fXa (oral form)
ximelagatran prevention of
venotrombolism - Direct inhibitors of fIIa
(oral form) dabigatran rivaroxaban
Ind prevention against DVT in postoperative
patients who underwent orthopedic
surgery
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DRUGS USED IN DISORDERS
OF HEMOSTASIS I. Drugs reducing processes
of hemostasis ANTIPLATELED AGENTS
ANTICOAGULANT DRUGS FIBRINOLYTICS
II. Drugs used in bleeding disorders
HEMOSTATICS
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-
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I. Drugs reducing processes of hemostasis
FIBRINOLYTICS (thrombolytics) rapidly lyse
thrombi by catalyzing the formation of the
protease plasmin from its precursor
plasminogen, 1st generation These drugs create
a generalized lytic state when administered i.v.
both protective
hemostatic thrombi and target thromboemboli are
broken down. Streptokinase - a protein
synthetized by streptococci that combines with
the proactivator of plasminogen.This enzymatic
complex catalyzes the conversion of inactive
plasminogen to active plasmin. Urokinase - a
human protein synthetized by kidney that
directly converts plasminogen to active plasmin.
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FIBRINOLYTICS
FIBRINOLYTICS
Plasminogen
Inhibition
Activation
Streptokinase

Blood proactivator
Blood activator
-

Antiactivators
urokinase
-

Activator

t-PA rt-PA
Plasmin


Thrombin
Fibrin split products
Degradation products
Fibrinogen
Fibrin
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Fibrinolytics
Plasmin formed inside a thrombus by these
activators is protected from plasma
antiplasmins, which allows it to lyse the
thrombus within. 2nd generation Anistreplase
(Plasminogen Streptokinase Activator Complex-
APSAC) consists of a COMPLEX of purified human
plasminogen streptokinase that has been
acetylated to protect the enzymes active site.
When administered, the acyl group spontaneously
hydrolazes freeing the activated
streptokinase-activator complex. This complex
allows for rapid i.v. injection,
greater clot
activity (less activity on free
plasminogen
in the blood) and
more thrombolytic activity.
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Fibrinolytics
Plasminogen is also activated endogenously by
tissue plasminogen activators -tPA These
activators preferentially activate plasminogen
that is bound to fibrin, which (in theory)
confines fibrinolytics to the formed thrombus
and avoids systemic activation. Human t-PA is
manufactured by means of recombinant DNA
technology. Reteplase modified rt PA
(recombinant technology)
that is able to
penetrate inside the thrombi
enhanced fibrinolytic activity ---rapid
reperfusion low
incidence of bleeding
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Fibrinolytics

• Unwanted effects
• bleeding
• may be treated with antifibrinolytics,
• fresh
  plasma or coagulation factors
• allergic reactions (streptokinase)
• Contraindications
• active internal bleeding
• haemorrhagic cerebrovascular disease
• bleeding diatheses
• pregnancy
• invasive procedures in which hemostasis is
  important
• recent trauma
• 
  

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Fibrinolytics

• thrombolytic i.v. therapy (in selected patients
  within a few hours on onset of symptoms)
• ind
• acute myocardial infarction
• acute thrombotic stroke
• deep vein thrombosis, pulmonary embolus,
  clearing
• thrombosed shunts and cannulas,
• acute arterial thromboembolism

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DRUGS USED IN DISORDERS
OF HEMOSTASIS I. Drugs reducing processes
of hemostasis ANTIPLATELED AGENTS
ANTICOAGULANT DRUGS FIBRINOLYTICS
II. Drugs used in bleeding disorders
HEMOSTATICS
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II. HEMOSTATICS
At phase of vasoconstriction
vasopressin
alpha sympatomimetics
At platelet phase Desmopressin acetate (arginin
vasopressin) the factor VIII activity
(in patients with mild hemophilia A,B)

At phase of coagulation plasma coagulation
factors vit K and protamin sulphate
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II. HEMOSTATICS
Antifibrinolytics tranexamic acid inhibits
plasminogen activation and thus prevents
fibrinolysis (i.v. or oral administration) aminoca
proic acid resembles tranexamic acid aprotinin
inhibits the proteolytic enzyme-plasmin ind.
overdose of fibrinolytics the
surgical procedures that cause an increase in
endogenous fibrinolytic agents
(liver transplantation) Unwanted
effects thrombotic complications resulting from
inhibition of fibrinolysis, which is a natural
mechanism of defense against the formation of
thrombus stroke, MI, coronary-bypass graft
occlusion
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ANTIFIBRINOLYTICS
Plasminogen
Inhibition
Activation
Various stimuli

Blood proactivator
Blood activator
aminocaproic acid tranexamic acid
-

-
T-PA
Activator

aprotinin
-
Plasmin


Thrombin
Degradation products
Fibrin split products
Fibrinogen
Fibrin
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Thank you for your
attention
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Chemical structure of vit.K and warfarin
ONa
O
C6H5
R
CHCH2COCH2
O
CH3
O
O
Warfarin (vitamin K antagonist)
Vitamin K (natural vitamin)
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TFPI
Protein C
Thrombomodulin Endothelial cells
VII
VIIa
TF
- TF
XIa
Protein Cact
IX
IXa
VIIIa
X
Xa

Inhibited by heparin
Va
Inhibited by oral anticoagulant drugs
II
IIa
Thrombin
Prothrombin
Down-regulated by protein Cact
Ia Fibrin clot
I Fibrinogen