Drugs affecting blood clotting
TomasGonec 7.11.2011
Blood clot
□ stops bleeding
□ necessary for homeostasis at physiological conditions
B
Blood clot formation - coagulation
INTRINSIC PATHWAY
Contact with damaged surface
HMWK&Prekallikrein
Kininogen Kallikrein
XII
EXTRINSIC PATHWAY
Trauma
Tissue Factor
VII
(Fibrinogen)   (Fibrin monomer) Soluble
*
Plasminogen
Plasmin
(Crosslinked Fibrin) Insoluble
Fibrin Degradation Products
Formed Clot
□ Thrombus - fixed on surface (vessel wall)
□ Embolus - free-floating clot
□ both can occlude vessels and cause ischaemia with necrosis of the tissue
Thrombotic conditions
□ often due to atherosclerotic vessel changes
□ anticoagulant therapy - prevention of clot forming
□ thrombolytic therapy - dissolving of already formed clots
11
Diseases connected with thrombotic conditions:
□ myocardium infarction
□ valvular hearth disease
□ angina pectoris
□ pulmonary embolism
□ cerebrovascular accident (stroke)
Oral anticoagulants
□ vitamin K antagonists
□ heparins
□ antiplatelet drugs
Vitamin K antagonists - coumarins
COO'
H2C CH2 —N-CH
H/6-o
rGiu
Descarboxy prothrombin (Proenzymes)
'OOCN ,COO" CH CH-, —N-CH
7=°
Gal
Prothrombin (Factor II)
(Y-Carboxyproenzymes\ Factors VII, IX, X Protein S and C /
Vitamin K dependent carboxylase
OH
Vitamin K (hydroquinone, KHa)
X-S2
C02 + o2
NAD(P)+
Blocked by Coumarins
Vitamin K 2,3-epoxide
X-(SH)j,
Vitamin K 2,3-quinone Reductase
X-(SH)2
NAD(P)H
Vitamin K 2,3-epoxide Reductase
X-S2
Blocked by Coumarins
Vitamin K (Quinone)
R =  —CH,CH=C
11
Coumarins: Structure-activity relationships
PhenpfOCOUmon DicOUmarol Ethylbiscoumacetate
11
Superwarfarin analogues-rhodenticides
Indandiones
B
Heparins
□ accelerates binding of antithrombin III (protease inhibitor) to activated IX, X, XI, XII factors, kallikrein and thrombin
□ chemically a mixture of sulfated mucopolysacharides
Forms of Heparins
□ High molecular weight heparin (HMWH) -unfractionated. Mr 5-30 kD. Individual response for therapy, monitoring necessary
□ Low molecular weight heparin (LMWH) -fraction of Mr 4-6 kD isolated from HMWH. Higher selectivity for Xa factor, better pharmacological properties
Heparinoids
□ synthetic analogues of heparin
□ sulfatated polysacharides of similar Mr
□ only external use (unguents, creams, gels) due to high system toxicity
Hirudin
□ protein of 65 aminoacids
□ originally isolated from medicinal leech, now used recombinant form
□ forms complex with thrombin
Antiplatelet drugs
Acetylosalicylic acid (aspirin)
□ cyclooxygenase inhibitor
Dipyridamole
□ adenosine uptake antagonist
□ in combination with warfarin
0 |^OH
Q
Dipyridamole
Ticlopidine and Clopidogrel
inhibitors of tromboxan-synthase
ch3
Ticlopidine (S)-Clopidogrel
Glycoprotein receptor antagonists
NH x H2N NH C 9	
	
	
Eptifibatide ♦	
H02G /—\                   /=\ V-NH HN^^(CH2)4-0-^^--^ o,;S-(CH2)3-CH3	
Tiroftban	
Thromboxan antagonists
j cooh &	
	a
oh	
Epoprostenol	Anagrelide
Thrombolytic drugs
□ physiological fibrinolytic agent - plasmin -non-specific protease enzyme digesting fibrin
□ activated from proenzyme plasminogen
Streptokinase
□ protein purified from haemolytic streptococcus bacteria
□ forms complex with plasminogen - active catalyzator of plasminogen to plasmin conversion
□ short biological half-time (30min)
□ often hypersensitivity reaction (from rash to anaphylaxis)
Anistreplase
□ prodrug of streptokinase with anisoyl groups acylated on lysine fragments
□ prolonged biological half-time (90min)
Urokinase
□ isolated from human fetal kidney cells
□ directly degrade fibrin and fibrinogen
□ very short half-time (15min)
□ no hypersensitive reactions
Alteplase, Reteplase
□ produced using recombinant technology
□ analogues of human plasminogen activator
□ specifity for already formed clots
□ extremely short half-time (5min)
□ administrated via continuous infusion
Ancrod, Batroxobin
□ snake poison proteases
□ non-specific effect by digesting both fibrin and coagulation factors
Coagulants
□ used in states with excessive bleeding caused by insufficient coagulation
Vitamin K
□ Vitamin Kl(phytonadion), K3 (menadion), water soluble K4 (menadione sodium diphosphate)
Vitamin K
□ used in avitaminose states
□ therapy of bleeding caused by vitamin K antagonists (including rhodenticides)
Protamine
□ group of simple proteins
□ specific antagonists of heparin
□ isolated from salmon sperm
□ often hypersensitive reactions
Aminocapronic and Tranexamic acid
□ completely inhibits plasminogen activation
H2N-CH2-CH2-CH2-CH2-CH2-COOH CH3-N---sr^A---COOH
Aminocaproic acid Tranexamic acid
Aprotinin
□ protease inhibitor blocking kallikrein and plasmin
□ useful in postoperative bleeding
Clotting factors
□ recombinant factors substituting physiological factors
□ used in chronical diseases like haemophylia
Plasma extenders
B
□ Physiological solution (0.9 % NaCl)
□ Ringer solutions (some additive minerals and lactate)
□ protein colloids (albumin, plasma protein fraction)
□ dextran polymers (branched glucose polymers produced by bacteria)