Anticoagulants and Thrombolytic Agents

8/2/2019 Anticoagulants and Thrombolytic Agents

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Coagulation cascade

After injury to a vessel wall, tissue factor is exposed on

the surface of the damaged endothelium.

The interaction of tissue factor with plasma factor VII

activates the coagulation cascade, producing thrombin by

stepwise activation of a series of proenzymes

The coagulation cascade is regulated by natural

anticoagulants, such as tissue factor pathway inhibitor

TFPI, the protein C and protein S system, and

antithrombin, all of which help to restrict the formation

of the hemostatic plug to the site of injury.

Effects of thrombin

converts soluble fibrinogen to fibrinactivates factors V, VIII, and XI, which generates more

thrombin

stimulates platelets

by activating factor XIII, thrombin favours the

formation of cross-linked bonds among the fibrin

molecules, stabilizing the clot

Activated platelets

An activated platelet exposes surface

receptors for specific clotting factors,

such as factor Va, and anionic

phospholipids that function as binding

sites for factor Xa.

An analogous system exists for

binding factor IXa.

Endogenous inhibitors of coagulation

antithrombin III

from a family of serine protease

inhibitors (serpins)

glycose aminoglycans (GAGs)

highly sulphated sugars bind to

antithrombin by ionic interaction

associated with surfaces of endothelial

cells and subendothelial structures

smaller heparin molecules inhibit Xa

more effectively

tissue factor pathway inhibitor

(TFPI)

inhibits Xa by forming a complex that

can also inhibit VIIa bound to TF, but

not free VII

important for blocking the effect of TF

where it is expressed on endothelial

cells and subendothelial structures

proteins C and Sthrombin in conjunction withthrombomodulin, activates protein CProtein C proteolytically cleaves VIIIa

and Va (major cofactors that helpproduce Xa and IIa), with protein Sacting as cofactorin septic patients, activated protein C(available as a recombinant product)inhibit DIVC that occurs in smallvesselsprotein C may down-regulateinflammatory cytokines

thrombomodulin

a constituent of the endothelial cell

membrane, very small amounts arepresent in blood

binds thrombin and begins the

sequence of protein C activation

functions as cell-based

inhibition of coagulation

probably facilitates thrombin

catabolism

Anticoagulants and thrombolytic agentsNC Hwang 2008


2/12

Thrombus formation at the site of damaged vessels

Platelet factors

platelet factor 1: coagulation factor V

platelet factor 2: thromboplastic material

platelet factor 3: platelet thromboplastin

platelet factor 4: antiheparin factor

platelet factor 5: fibrinogen coagulation factor

platelet factor 6: antifibrinolytic factor

platelet factor 7: platelet cothromboplastin

Platelet membrane glycoproteins

GP Ia: receptor for subendothelium

GP Ib: receptor for von Willebrand

GP IIb: receptor for von Willebrand, fibrinogen

GP IIIa: receptor for von Willebrand, fibrinogen

Prothrombin time

monitoring of extrinsic coagulation pathway

normal range between 9 to 15 seconds

"normal" varies according to batch of thromboplastin in

test reagent in different laboratories, hence the use ofInternational Normalised Ratio (INR)

for a person on full anticoagulant therapy, the PT should

be 2 to 3 times the laboratory "control" value (INR of 2-

3)

prolonged PT (more than 3 times control value)

bile duct obstruction

cirrhosis

disseminated intravascular coagulation

hepatitis

malabsorption

warfarin therapy

> 10% deficiency in any of the following

Vitamin K, VII, X, II, V, I

Partial thromboplastin time

monitoring of intrinsic and common coagulation

pathways

partial thromboplastin time (PTT):3045 s

activated partial thromboplastin time (APTT):2539 s

value will vary between laboratories

patients receiving anticoagulant therapy usually will

have value within 1.5 to 2.5 times control values

not valid for patients on low molecular weight heparin

therapy (anti Xa heparin assay)

prolonged PTT may indicate

cirrhosis

disseminated intravascular coagulation (DIC)

factor XII deficiency

hemophilia A (factor VIII deficiency)

hemophilia B (factor IX deficiency)

hypofibrinogenemia

malabsorption (inadequate absorption of

nutrients from the intestinal tract)

von Willebrand's disease

lupus anticoagulant

decreased aPTT can occur due to:digitalis

tetracyclines

antihistamines

nicotine

elevated factor VIII

tissue inflammation or trauma

Fibrinolytic system



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DRUGS USED IN COAGULATION DISORDERS

ANTICOAGULANTS

Heparina heterogeneous groupa member of the heparan sulphate family of complexsugars classified under glycosaminoglycans

glycosaminoglycans or mucopolysaccharides

are polymers of repeating disaccharideswithin the disaccharides, the sugars

tend to be modified, with acidic

groups, amino groups, sulfated

hydroxyl and amino groups

tend to be negatively charged, because

of the prevalence of acidic groups

heparan sulphate family of complex sugars is

composed of long chains of alternating

disaccharide units of uronic acid (glucuronic

and iduronic acid) and glucosamine residues

the backbone structure is thendecorated by with complex patterns of

sulphate and carboxyl groups at various

positions, giving rise to a very strongly

negative charged molecule.

strongly acidic because of its content of covalently

linked sulfate and carboxylic acid groups (heparin

sodium)

has an extended helical conformation due to

charge repulsion by the many negatively

charged groups

naturally occurring in the secretory granules of mastcells

has no anticoagulation effect by itself

biologic activity is dependent upon the plasma protease

inhibitor, anti-thrombin III (AT III) (heparin cofactor)

a specific pentasaccharide sequence containing a 3-O-

sulphated glucosamine residue forms a high-affinity

binding site for AT III

AT III is one of the many naturally occurring

inhibitors in coagulation but its action is slow

small amounts of heparin (with AT III) inhibit

thrombosis by inactivating activated Factor X

(Xa) and inhibiting the conversion of

prothrombin to thrombin (II to IIa)

tight binding of heparin molecule to AT III

causes a conformational change in this inhibitor,

which exposes the active binding site of

antithrombin III for more rapid interaction with

the proteases (activated clotting factors) to

inhibit the enzymes

in the absence of heparin, formation of heparin-

antithrombin-protease complexes is slow, in the presence

of heparin, they are accelerated 1000-fold

heparin catalyses the antithrombin-protease reaction

without being consumed

once the antithrombin-protease complex is

formed, heparin is released intact for renewed

binding to more AT III

heparin-antithrombin III complex inactivates

serine esterases

factors XIIa, XIa, Xa, IXa, IIa

plasmin

kallilrein

only unbound Xa is sensitive to heparin activity

Xa bound to platelets in the prothrombinase

complex is protected from the heparin actiononce active thrombosis has developed, larger amounts of

heparin inhibit further coagulation by inactivating

thrombin (IIa) and preventing the conversion of

fibrinogen to fibrin (I to Ia)

decreased platelet aggregation

reduction of platelet membrane receptors for

von Willebrand factor and fibrinogen (Ia)

inhibition of VIIIa, Va

facilitating the release of tissue plasminogen

activator (tPA), resulting in an increase in

plasmin and D-dimer concentrations, both ofwhich interfere with platelet aggregation

increased platelet aggregation

binding of antiplatelet IgG antibodies to

platelet-bound heparin, activates platelets and

induces platelet clumping (heparin-induced

thrombocytopaenia, HIT)

inhibition of VIIa-TF complex

by releasing TFPI from endothelial cells, renal

cells, carcinoma cells and lipoprotein fraction of

plasma

TFPI also inhibits Xa on TF bearing cellreleases lipoprotein lipase from capillary endothelial

surfaces

the enzyme hydrolyzes triacylglycerols in

chylomicrons, very-low-density lipoproteins,

low-density lipoproteins, and diacylglycerols

inhibits growth of capillary endothelial cells but

potentiates the activity of acid fibroblasts growth factors

on these cells



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commercial preparations

consists of repeated sulphated mucopolysaccharides

D-glucosamine-L-iduronic acid, and

D-glucosamine-D-glucuronic acid

source

porcine intestinal mucosa (higher potency)

bovine lung

partial substitution of acidic protons of the sulfate units

by

Na+ (as heparin sodium)

Ca++ (as calcium heparin)

Li+ (as lithium heparin)

used in vitro as an anticoagulant for blood

samples

pH adjustment (between 5.0 and 7.5)

titrated with HCl or NaOH

standardization of activity

regular heparin consists of a family of

molecules of different molecular weights, the

correlation between the concentration of a given

heparin preparation and its effect on coagulationoften is low

therefore standardized as units of activity by

bioassay

heparin sodium must contain at least 120 USP

units per milligram

1 U stops 1 ml of citrated sheep plasma from

clotting for 1 hour after the addition of 0.2 ml of

1% calcium chloride

high molecular weight (HMW) fractions

with high affinity for AT III, markedly inhibit

blood coagulationfractions have a MW range of 5 000-30 000

low molecular weight (LMW) fractions

MW 1 000-10 000 (1-10kDa, mean 4.5 kDa)

less effect on antithrombin III

activity dependent on number of

monosaccharide units per molecule

< 8, no significant antithrombotic

activity

8-18, potentiate inhibition of factor Xa

>18, potentiate inhibition of both

factor Xa and thrombinisolated from standard heparin

by gel filtration chromatography

by differential precipitation with

ethanol

by partial depolymerization with

nitrous acid

by alkaline degradation of heparin

benzyl ester / beta elimination

degradation (enoxaparin Na)

by enzymatic degradation

compared with regular heparinincreased bioavailability after

subcutaneous administration

less frequent dosing requirements

units of reference

milligrams for enoxaparin

anti-factor Xa units for dalteparin and

danaproid

indications

prevention of deep venous thrombosis

after hip replacement surgery

treatment of acute deep vein

thrombosis

prophylaxis for ischaemic

complications in unstable angina and

non-Q-wave myocardial infarction

pharmacokinetics

absorption

not absorbed from the intestinal mucosa,

therefore administered parenterally (continuous

infusion, intermittent intravenous injection, deep

subcutaneous injection)

onset of action

after intravenous administration, immediate

after subcutaneous administration, delay of 1-2

hours

clearance

degraded primarily by reticuloendothelial

system, and heparinase

small amount of undegraded heparin appears in

urine

t

dose-dependent

100 U/kg, 1 hour

400 U/kg, 2.5 hours

800 U/kg, 5 hours

shortened in patients with pulmonary embolism

prolonged in patients with hepatic cirrhosis or

renal failure

LMW heparins have longer biological half-lives than do standard heparin

adverse effects

bleeding

monitor partial thromboplastin time (PTT)

elderly women and patients with renal failure

are more prone to haemorrhage

platelet dysfunction

thrombocytopenia (HIT)

platelet count of less than 50% of pretreatment

value or


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contraindications

hypersensitivity

active bleeding

haemophilia

thrombocytopaenia and history of HIT

purpura

severe hypertension

intracranial haemorrhage

infective endocarditis

active tuberculosis

ulcerative lesions of gastrointestinal tract

threatened abortion

visceral carcinoma

advance hepatic or renal disease

during or after surgery of brain, spinal cord, or eye

undergoing lumbar puncture or regional anaesthesia

blocks

administration and dosages

used in pregnant women only when clearly indicated

established venous thrombosis

maintain plasma concentration of 0.2 U/ml toprolong the PTT to INR 2-2.5

initial bolus injection of 5000-10000 U,

followed by infusion of 10-15 U/kg/h

with acute pulmonary embolism,

larger doses require during the first few

days because of increased heparin

clearance

intermittent administration, 75-100 U/kg every

4 hours

heparin resistance - causes

increased serum concentration of other (acute reactant)proteins that have affinity for heparin

fibroblast growth factors (FGFs)

vascular endothelial growth factor (VEGF)

heparin-binding EGF-like growth factor

hepatocyte growth factor (HGF)

transforming growth factor-beta (TGF-beta)

interferon-gamma (IFN-gamma)

platelet-derived growth factor (PDGF)

platelet factor-4 (PF-4)

interleukin-8 (IL-8)

macrophage inflammatory protein-1 (MIP-1)interferon-gamma inducible protein-10 (IP-10)

insulin-like growth factors I or II

fibronectin

laminin

histidine-rich glycoprotein vitronectin

increased concentration of factor VIII, a cofactor that

increases the proteolytic activity of IXa

congenital deficiency of AT III (concentration less than

50% of normal), may be precipitated by pregnancy,

infection or surgery

acquired deficiency of AT III (concentration less than25% of normal), may occur in patients with hepatic

cirrhosis, nephrotic syndrome, disseminated intravascular

coagulation

accelerated clearance of heparin, as may occur with

massive pulmonary embolism

reversal of heparinisation

discontinuation of the drug

protamine sulphate

highly basic peptide that combines with heparin

as an ion pair to form a stable complex devoid

of anticoagulant activity

for every 100 U of heparin remaining in the

patient, 1 mg of protamine sulphate is

administered intravenously

excess protamine has an anticoagulant effect

binds to platelets and fibrinogen

metabolized by N-carboxypeptidase

Enoxaparin

obtained by alkaline degradation of heparin benzyl ester

approximately one-third molecular size of standard

heparin

Fondaparinux sodium

synthetic and specific inhibitor of activated factor X

(Xa)

molecular weight is 1728

supplied as a clear and colorless liquid with a pH

between 5.0 and 8.0

mechanism of action

antithrombin III-mediated selective inhibition of factor

Xa, and potentiates (about 300 times) the innate

neutralization of factor Xa by AT III

does not inactivate thrombin and has no known effect on

platelet function

does not bind significantly to other plasma proteins

(including platelet factor 4) or red blood cellsabsorption

rapidly and completely absorbed after administration by

subcutaneous injection, bioavailability is 100%

distribution

in healthy adults, volume of distribution of 7-11 L

clearance

in healthy individuals up to 75 years of age, up to 77%

of a single subcutaneous or intravenous fondaparinux

dose is eliminated in urine as unchanged drug in 72 hours

25% lower in patients over 75 years of age

elimination half-life is 17-21 hourstotal clearance is approximately lower in patients with

renal impairment

drug interactions

concomitant use of oral anticoagulants (warfarin),

platelet inhibitors (acetylsalicylic acid), NSAIDs

(piroxicam) and digoxin did not significantly affect the

pharmacokinetics/pharmacodynamics of fondaparinux

sodium

does not influence the pharmacodynamics of warfarin,

acetylsalicylic acid, piroxicam, and digoxin, nor the

pharmacokinetics of digoxin at steady statedoes not bind significantly to plasma proteins other than

AT III, no drug interactions by protein-binding

displacement are expected



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Warfarin

oral anticoagulant introduced as rodenticide in 1948

Wisconsin Alumni Research Foundation - arin

discovery of anticoagulant substance formed in spoiled

sweet clover silage which produced a deficiency of

plasma prothrombin and haemorrhagic disease in cattle

toxic agent identified as bishydroxycoumarin

and synthesized as dicoumarol

structure

4-hydroxycoumarin residue, with a non-polar carbon

substituent at the 3-position, is the minimal structural

requirement for activity

this carbon is asymmetrical in warfarin

commercial preparations are racemic

mixture of 2 enantiomorphs

levorotatory S-warfarin

dextrorotatory R-warfarin

potency: S-warfarin > R-warfarin, 4:1

mechanism of action

warfarin prevents the -carboxylation of glutamate

residues in factors II, VII, IX, and Xby blocking the reduction of inactive vitamin K

epoxide (by vitamin K epoxide reductase) back

to its active hydroquinone form

results in incomplete molecules that are

biologically inactive in coagulation

role of vitamin K

post-ribosomal modification of factors II, VII, IX, and

X, and the endogenous anticoagulant protein C and S in

the liver

involves -carboxylation of glutamate residuesin them

the carboxyl-glutamyl residues are responsible for the

binding of Ca++ which are necessary for the binding of

the activated factors to phospholipid vesicles

this process is coupled with the oxidative deactivation of

vitamin K

in vitamin K deficiency, inactive precursors are

liberated

anticoagulant effects

8-12 hour delay in the action of warfarin, duration of

action 2-5 daysanticoagulant effect of warfarin results from a balance

between partially inhibited synthesis and degradation rate

of the 4 vitamin K-dependent clotting factors

t: 6 h (VII), 24 h (IX), 36 h (X), 50 h (II)

large initial doses of warfarin (0.75/kg) hasten the onset

of anticoagulation effect, beyond this dosage, the speed

of onset is independent of the dose size; only effect of a

large loading dose is the prolongation of t of the drug

pharmacokinetics

absorption

acidic, available as a sodium salt

rapid oral absorption, 100% bioavailability

decreased in malabsorption

detectable in plasma within 1 hour of oral

administration

peak plasma concentration in 2-8 hours

crosses placenta

distribution

99% of racemic warfarin bound to plasma

albumin, which may contribute to its

small Vd (the albumin space) 0.14L/kg

clearance

0.045 ml/kg/min

transformed by CYP 1A2, CYP2C9 into

inactive metabolite by the liver and kidney

long t of 25-60 hours in plasma,

prolonged with liver disease

excreted via urine and stool

adverse effects

crosses placenta readily

causing haemorrhagic disorder in the foetus

affecting -carboxyglutamate residues in foetal

bone and blood proteins and causing birth defect

characterised by bone malformation

cutaneous necrosis

sometimes occur during the first week of

therapy resulting from venous thrombosis

due to reduced activity of protein C

(endogenous anticoagulant)

rarely same process causes haemorrhagicinfarction of the breast, fatty tissues, intestine,

and extremities


start with small daily dose of 5-10 mg, may be up to 40

mg; initial adjustment of prothrombin time takes about 1

week

maintenance dose of 5-7 mg/day, may be up to 15

mg/day

INR of 2.5-3.5 for patients with prosthetic heart valves

drug interactions

pharmacokinetic mechanismsincreasing or decreasing anticoagulant effect

and the risk of bleeding by

enzyme induction or inhibition

variation in plasma protein binding

increasing activity of warfarin

stereoselective inhibition of oxidative

metabolism of S-warfarin, resulting in

hypoprothrombinaemia

pyrazolones, phenylbutazone,

metronidazole, fluconazole,

trimethoprim-sulpha methoxazoleinhibition of metabolism of warfarin

amiodarone, disulfiram, cimetidine,

chloramphenicol

displacement of albumin-bound warfarin,

increasing the free fraction

pyrazolones, phenylbutazone,

sulfinpyrazone, NSAID, chloral

hydrate, mefenamic acid



7/12

decreasing activity of warfarin

induction of hepatic enzymes that metabolise

warfarin

barbiturates, rifampicin, alcohol

reduction in absorption and bioavailability

cholestyramine binds warfarin in the

intestine

increased albumin binding

pharmacodynamic mechanisms

synergism(impaired haemostasis, reduced

clotting factor synthesis in hepatic disease,

heparin, NSAIDs)

competitive antagonism (vitamin K)

altered physiologic control loop for vitamin K

(hereditary resistance to oral anticoagulant

augmentation of anticoagulant effect

inhibition of platelet function

pyrazolones, phenylbutazone, aspirin

increasing turnover of clotting factors

liver disease, hyperthyroidism

inhibition of activity of VIIa, IXa, Xa, IIaheparin, (prolonging prothombin time)

vitamin K production

elimination of vitamin K producing

bacteria in gastrointestinal tract by

third generation cephalosporins

direct inhibition of vitamin K epoxide

reductase

third generation cephalosporins

reduction of anticoagulant effect

increase synthesis of clotting factors with

vitamin Kincrease supply of clotting factors with

transfusion of fresh frozen plasma

clotting factor concentration through

haemoconcentration with diuretics

hereditary resistance to warfarin via mutation

of vitamin K epoxide reductase

decreasing turnover rate of clotting factors

hypothyroidism

reversal of antocoagulant effects

disappearance of anticoagulant effect is due toreestablishment of normal activity of the

clotting factors

does not correlate with plasma concentration of

warfarin

depends on the degree of correction required

stopping warfarin alone with or without

large doses of vitamin K (phytonadione)

50 mg infusion

fresh frozen plasma

factor IX concentrates

whole blood transfusion

Direct thrombin inhibitor

bind directly to thrombin and block its interaction with

its substrates

recombinant hirudins, bivalirudin, and

ximelagatran

parenteral DTIs:

hirudin and argatroban for the treatment of

heparin-induced thrombocytopenia

bivalirudin as an alternative to heparin in

percutaneous coronary intervention, and

desirudin as prophylaxis against venous

thromboembolism in hip replacement

Hirudin

source

Hirudo medicinalis leeches,

powerful and specific thrombin inhibitor

recombinant DNA

mechanism of action

binds to active site of thrombin

can reach and inactivate fibrin-bound thrombin

little effects on platelets or bleeding time

administration

parenterally

monitored by partial thromboplastin time

Ximelagatran

first oral direct thrombin inhibitor to be introduced

a prodrug, its active metabolite is melagatran which

directly inhibits thrombin

ximelagatran developed to enhance bioavailability of

melagatran, the molecules of latter are charged and

become highly hydrophilic at intestinal pH, resulting in

low absorption

melagatran can also be given by injection

melagatran resembles a peptide sequence on

fibrinogens A- chain, where thrombin-inducedcleavage occurs

it binds reversibly to the active site of thrombin and

inhibits the normal function of thrombin, including both

free and clot-bound thrombin

the ability to bind clot-bound thrombin is an

advantage since clot-bound thrombin may retain

its enzymatic activity and continue to stimulate

the coagulation cascade

regulatory approval for ximelagatran in France for the

prevention of venous thromboembolic events in major

orthopaedic (hip or knee replacement) surgerydoes not have the same difficulties with dose adjustment

or drug interaction as warfarin does

no known antidote

pharmacokinetics

rapidly absorbed after oral administration, peak

concentration Cmax achieved 1 h after administration

has a rapid onset and offset of action and shows low

potential for food and drug interactions

oral bioavailability approximately 20%, compared with

3%-7% for melagatran

ximelagatran Vd 2.53L/kgpharmaokinetics of melagatran described as linear, first-

order, one compartment model

melagatran excreted unchanged via kidneys, t 3h

renal clearance rate

young 7.7L/h, elderly 5 L/h

affected in patients with severe renal

impairment, defined as creatinine

clearance rate of


8/12

adverse effects

nausea, diarrhoea, headache

bleeding, but not worse than with enoxaparin or

dalteparin

raised hepatic ALT and bilirubin concentrations

contraindications

renal, and hepatic impairment

pregnancy

infant and children

precautions

lactating women

main properties and pharmacokinetic characteristics

FIBRINOLYTIC DRUGS

mode of action

rapid lysis of haemostatic thrombus and target

thromboemboli by catalysing the formation of serine

protease plasmin from its precursor zymogen

plasminogencan cause a generalized lytic state after

intravenous administration

(zymogen = inactive precursor of proteolytic

enzyme)

activation of free circulating plasminogen

streptokinase

urokinase

activation of fibrin bound plasminogen

anistreplase

alteplase

reteplasetissue plasminogen activator (t-PA)

indications

multiple pulmonary emboli that are massive enough to

require surgical intervention

central deep vein thrombosis of the superior venous

cava, iliofemoral veins

coronary thrombolysis after acute myocardial infarction

peripheral arterial disease

Streptokinase

exotoxin of-haemolytic streptococci

antigenic

forms a stable, noncovalent 1:1 complex with free

circulating plasminogen

produces a conformational change that exposes the

active site on plasminogen that cleaves arginine 560 on

free plasminogen molecules to form free plasmin

complex is not inhibited by 2-antiplasmin

not fibrin specific, readily induces a systemic lytic state

t 40-80 minutes

adverse effects

bleeding, allergic reactions, fever, anaphylaxis

Anistreplase

anisolyated plasminogen streptokinase

activator complex, APSAC

a complex of purified human plasminogen and

bacterial streptokinase

lys-plasminogen has been acylated at its

catalytic site to protect the enzymes active site

when administered, the acyl group

spontaneously hydrolyses, allows the

plasminogen-streptokinase complex to bind to

fibrin prior to activation,

this modification confers clot selectivity

advantages

allows for rapid intravenous injection

greater clot selectivity

Tissue plasminogen activator

preferentially activates plasminogen that is bound tofibrin, several hundredfold more rapidly than free

plasminogen in the circulation

theoretically confines fibrinolysis to the formed

thrombus and avoids systemic activation

binds to fibrin via lysine binding sites at its amino

terminus

metabolised by liver, t 5-10 minutes

produced by recombinant DNA technology

alteplase is unmodified t-PA

reteplase is t-PA from which several amino

acids have been deleted

Urokinase

human enzyme synthesized by kidney, therefore not

antigenic

directly converts free plasminogen to plasmin

lacks fibrin specificity, readily induces a systemic lytic

state

metabolised by liver, t of 15-20 minutes

Prourokinase

a zymogenic plasminogen activator, a precursor ofurokinase

binds to fibrin before activation

has selectivity for clots



9/12


streptokinase (US$_00)

intravenous infusion, loading dose 250 000 U

to overcome plasma antibodies directed against

the protein (from prior streptococcal infection),

followed by maintenance dose of 100 000

U/hour for 24-72 hours

follow with full heparinisation as plasminogen

is exhausted

can act as antigen, patients with antibodies to

streptokinase can develop fever, allergic

reactions, therapeutic resistance

urokinase (US$_000)

intravenous infusion, loading dose 1000 to

4500 U/kg over 10 minutes, followed by

maintenance dose of 4400 U/kg/hour for 12

hours

alteplase (t-PA) ($_000)

accelerated regime for coronary thrombolysis

intravenous infusion, loading dose 15 mg

followed by 0.75mg/kg over 30 minutes(maximum 50mg), followed by 0.5mg/kg

(maximum 35mg) over the following hour

reteplase ($_000)

administered as 2 intravenous bolus injections

of 10 U each separated by 30 minutes

anistreplase ($_000)

single intravenous bolus injection of 30 U over

3-5 minutes

ANTITHROMBOTIC DRUGS

prevention of vascular events among patients withtransient ischaemic attacks

complete strokes

angina pectoris

4 main groups

cyclo-oxygenase inhibitors: e.g. aspirin

increasing platelet cAMP:

by stimulation of adenylyl cyclase:

adenosine

by inhibition of phosphodiesterase:

dipyrimadole

ADP receptor antagonists: e.g. clopidogrelGP IIb,IIIa blockers: tirofiban, abciximab

target sites of antithrombotic drugs on the platelet

Cyclooxygenase inhibition

aspirin

inhibition of the synthesis of thromboxane A2

by irreversible, covalent acetylation of a serine

residue near the active site of cyclooxygenase

the anuclear platelet cannot synthesize new

proteins or enzymes during its 7-10-day life-

span

repeated doses produce a cumulative effect on

platelet function

maximally effective as an antithrombotic agent

at doses of 160mg to 320 mg/day

higher doses inhibit the production of

prostacyclin, an antithrombotic eicosanoid

produced by the endothelium

prolongs bleeding time

other NSAIDS

other salicylates and other nonsteroidal anti-

inflammatory drugs also inhibit cyclooxygenase

but have a shorter duration of inhibitory action

because they cannot acetylate cyclooxygenase,

therefore their action is reversible

Increasing platelet cAMP

following platelet activation, Ca++ is released from its

storage sites (platelet dense tubular systems) to the

platelet cytoplasm resulting in an increase of cytosolic

free Ca++

Ca++ mobilization is directly involved in

platelet activation and Ca++ is an important

second messenger for signal transduction in

plateletscAMP is another second messenger which opposes the

effect of Ca++by causing sequestration of cytosolic Ca++

to the Ca++ storage sites

agents which increase cAMP will suppress platelet

activation

stimulation of platelet adenylyl cyclase: action

of adenosine on platelet A2 receptor

inhibition of platelet phosphodiesterase:

dipyridamole

does not prolong bleeding time

only current recommendation is for

primary prophylaxis of thromboemboli

in patients with prosthetic heart valves,

and is given in combination with

warfarin

dipyridamole is metabolized in the

liver and has a terminal half-life of 10h



10/12

ADP receptor antagonism

Ticlopidine

a thienopyridine derivative, interferes selectively with

ADP-induced transformation of GPIIb/IIIa complex

expression in activated platelets

it also inhibits platelet aggregation induced by thrombin,

collagen, arachidonic acid, platelet-activating factor,

prostaglandin endoperoxides, thromboxane A2-like

substance, serotonin, and epinephrine

pharmacokinetics

absorption

well absorbed after oral administration

effect within 48 hours

maximal effect after approximately 3 to 5 days

activity still present 72 hours after last dose

absorption decreased by concurrent antacid

therapy

metabolism

rapidly and extensively metabolised in liver

and excreted in urineone of its metabolite is active

half-life at steady state is 4-5 days

effects

prolongs bleeding time, maximum effect after several

days of treatment

antiplatelet activity persists for a week or longer after

treatment is discontinued

possibly due to action of active metabolite

act independent of aspirin with no effect on eicosanoid

metabolism

adverse effects

gastrointestinal (20%): nausea, dyspepsia, diarrhoea

haemorrhage (5%)

bone marrow suppression

leucopenia (1%): detected by regular

monitoring of white cell count during the first 3

months of therapy

thrombocytopenia

agranulocytosis

aplastic anaemiacholestatic jaundice

elevated serum cholesterol concentration

rashes

indications

prevention of thrombosis in cerebral vascular and

coronary artery disease

for patients who are unable to tolerate aspirin

Clopidogrel

analogue of ticlopidine, another ADP antagonist from

the thienopyridine group that inhibits ADP and thrombin-

induced platelet aggregation

a prodrug, activated by cytochrome P450 predominantly

by CYP3A4 (less by CYP3A5) to a metabolite that

inhibits ADP-induced platelet aggregation

by binding the ADP receptor the drug selectively

reduces the number of functional ADP receptors

mediating the inhibition of stimulated adenylate cyclase

inhibits the binding of fibrinogen to its platelet

receptor, the GPIIb/IIIa integrin

it does not modify the GPIIb/IIIa complex

after oral administration, clopidogrel is rapidly absorbed

and undergoes metabolic activation by CYP3A4 in the

liver

antiplatelet activity of clopidogrel can be inhibited by

the CYP3A4 substrates erythromycin, troleadomycin,

and HMG-CoA reductase inhibitors (atorvastatin,

cerivastatin, lovastatin, and simvastatin) and enhanced by

the CYP3A4 inducer rifampin

co-administration of HMG-CoA reductase

inhibitors will diminish the activation of

clopidogrel

the principal circulating metabolite is an inactive

carboxylic acid derivative

has an 8 hour elimination half-life, but the

pharmacologic half-life is relatively long and it takes 4 to

7 days of administration to reach a steady state effect on

platelets

side effects include thrombocytopenia, neutropenia

clopidogrel-induced platelet inhibition persists severaldays after withdrawal of the drug and diminishes in

proportion to platelet renewal

in comparison with ticlopidine, clopidogrel is more

potent, with less degree of neutropenia

clopidogrel is significantly more active than aspirin.

compared with aspirin, clopidogrel has less

severe gastrointestinal bleeding but more severe

rash incidence

Platelet GP IIb/IIIa receptor antagonism

mechanism of actionblocks platelet receptors for integrin and fibrinogen

adverse effects

bleeding

immunogenicity

thrombocytopenia

in approximately 0.1% to 0.5% of patients,

platelet count of


11/12

free unbound abciximab undergoes rapid proteolytic

degradation, resulting in a 10- to 15-minute plasma half-

life

once bound to platelet receptors, resolution of

abciximab blockade is prolonged

50-60% residual inhibition remains 24 hours after

terminating the infusion

effective or biologic half-life for abciximab is estimated

to be > 12 to 24 hours

indications

used together with aspirin and heparin as adjuvant

therapy in patients undergoing high-risk angioplasty and

atherectomy

Integrelin

synthetic peptide with high affinity for the GP IIb/IIIa

integrin receptor protein

for prevention of thrombosis in percutaneous coronary

angioplasty

Eptifibatide and tirofiban

binds selectively to GP IIb/IIIa receptor

renally excreted, no active metabolites

half-life of 1.5 to 2.5 hours

rapidly dissociate from glycoprotein receptors, with

platelet aggregation returning to normal within 4 hours

after discontinuation of the drug



12/12

Drugs used in bleeding disorders

correction of prothrombin activity: vitamin K

plasma fractions: factors VIII, IX, and I

fibrinolytic inhibitors: aminocaproic acid, tranexamic

acid

serine protease inhibitor: aprotinin

CORRECTION OF PROTHROMBIN ACTIVITY

Vitamin K

being lipid soluble, vitamin K1 and K2 require bile salts

for absorption from the intestinal tract

available as 5 mg tablet, or 50 mg ampoule

effect delayed for 6 hours, completed by 24 hours when

treating depression of prothrombin activity after warfarin

therapy or vitamin K deficiency

intravenous infusion must be slow, rapid infusion can

cause dyspnoea, chest and back pain, even death

indications

correction of prothrombin activity

after warfarin therapy

vitamin K deficiency in premature infants, inhospitalised patients in intensive care units

because of poor diet, parenteral nutrition, recent

surgery, multiple antibiotic therapy, uraemia

severe hepatic failure results in loss of protein synthesis

and a haemorrhagic diathesis that is unresponsive to

vitamin K

FIBRINOLYTIC INHIBITORS

target sites

Aminocaproic acid

chemically similar to lysine, is a synthetic inhibitor of

fibrinolysis

mechanism of action

binds to lysine residues on plasminogen and plasmin

competitively inhibits plasminogen activation

blocks binding of plasmin to fibrin

pharmacokinetics

rapidly absorbed orally

cleared from the body via the kidney, 50% excretedunchanged in the urine within 12 hours

indications

haemophilia

bleeding from fibrinolytic therapy

prophylaxis for rebleeding from intracranial aneurysms

postsurgical gastrointestinal bleeding

postprostatectomy bleeeding

adverse effects

intravascular thrombosis from inhibition of plasminogen

activator

hypotension

ureteral obstruction by clot formation in patients with

haematuria

myopathy and muscle necrosis

abdominal discomfort

diarrhoea

nasal stuffiness

Tranexamic acid

trans-amino-methyl-cyclo-hexanoic acid (AMCHA)

analog of aminocaproic acid and has the same properties

potency increased by factor of 6-10 due to the distance

between the 2 function groups in the AMCHA molecule

is fixed by a cyclic structure

mechanism of action

occupies the lysine binding site of the plasminogen

molecule producing a conformational change in the

molecule, resulting in a fibrin polymer with greater

resistance to natural fibrinolysis

plasminogen activators when released, find less

substrate that can be converted to plasmin

dosing

intravenously, 10-15 mg/kg 2-3 times a day

oral dose 1-1.5g up to 4 times a day

SERINE PROTEINASE INHIBITORS

Aprotinin

originally found to be a kallikrein inhibitor (1930) and

trypsin inhibitor (1936)serine protease inhibitor (serpin) that

inhibits fibrinolysis by free plasmin

inhibits plasmin-streptokinase complex in

patients who received the thrombolytic agent

mechanism of action

fits into enzyme where the contact region for the normal

enzyme substrate is located

forms 1:1 complexes with the enzymes which include

trypsin, kallikreins from organs, tissues and

plasma, and plasmin

aprotinin acts as pseudo-substrate that prevents furtherproteolytic activity while it remains tightly bound to the

enzyme

administration and dosage

aqueous solution is stable at room temperature without

loss of activity

historical reasons, quantities and concentrations

expressed as kallikrein inactivator units KIU

administered by infusion

4 M results in 100% plasmin inhibition

15M results in only 90% kallikrein inhibition

t is 5-8 hoursindications

patients at high risk of excessive bleeding

cardiac reoperations

adverse effects

anaphylaxis

first exposure, 6 months

Drugs used in Bleeding DisordersNC Hwang 2008

Documents

Anticoagulants and Thrombolytic Agents