2016-01-24
Drugs affecting
coagulation
• Thrombosis – pathological formation of a
„haemostatic” plug within the vasculature in the
absence of bleeding
• Rudolph Virchow’s triad defined three
predisposing factors: injury to the vessels wall,
altered blood flow and abnormal coagulability of
the blood
Definitions
• Haemostasis – arrest of blood loss from damaged
blood vessels and is essential to life
• A wound causes vasoconstriction, acompanied by
adhesion and activation of platelets and finally
fibrin formation
• Platelet activation leads to the formation of a
haemostatic plug, which stops the bleeding and is
subsequently reinforced by fibrin
• Thrombus – forms in vivo, should be
distinguished from a clot, which forms in
static blood in vitro
• Clots are amorphous, consisting of a diffuse
fibrin meshwork in which red and white
blood cells are trapped indiscriminately
• Arterial thrombus – is composed of so-called
„white thrombus” consisting of platelets and
leucocytes in a fibrin mesh
Drug therapy
• Venous thrombus – is composed of „red
thrombus” and consists of a small white head
and a large jelly-like red tail, similar in
composition to a blood clot, which streams
away in the flow
• Thrombus can break away, forming an embolus;
this may lodge in the lungs or, if it comes from the
left heart or a carotid artery, in the brain or other
organs, causing death
• Drugs affect haemostasis and thrombosis in three
distinct ways, by affecting:
- blood coagulation
- platelet function
- fibrin removal (fibrinolysis)
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Blood coagulation
• Blood coagulation means the conversion of fluid
blood to a solid gel or clot
• The main event is the conversion by thrombin of
soluble fibrinogen to insoluble strands of fibrin,
the last step in a complex enzyme cascade
There are two pathways in the cascade:
- the extrinsic pathway, which operates in vivo
- the intrinsic pathway or contact pathway, which
operates in vitro
Both pathways result in activation of factor X,
which then converts prothrombin to thrombin
• PL is provided by activated platelets adhering to
the damaged vessel
• Some factors promote coagulation by binding to PL
and a serine protease factor
• Blood coagulation is controlled by:
- Enzyme inhibitors (Antithrombin III)
- Fibrinolysis
Fibrin formation
• The clotting system consists of a cascade of
proteolytic enzymes and cofactors
• Inactive precursors are activated in series , each
giving rise to more of the next
• The last enzyme – thrombin – derived from
prothrombin (II), converts soluble fibrinogen (I) to
an insoluble meshwork of fibrin in which blood
cells are trapped, forming the clot
• Calcium ions and a negatively charged
phospholipid (PL) are essential for three
steps, namely the actions of:
1. Factor IXa on X
2. Factor VIIa on X
3. Factor Xa on II
Drugs are used to modify the cascade
either when there is a defect in
coagulation or when there is
unwanted coagulation
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Coagulation defects
VITAMIN K
• Genetically determined deficiencies of clotting
factors are rare
• Example are classical haemophilia (lack of factor
VIII, and an even rarer form of haemophilia
(haemophilia B or Christmas disease) caused by
lack of factor IX
• Acquired clotting defects are more common than
hereditary. Liver disease, vitamin K deficiency and
excessive oral anticoagulant therapies
• Fat-soluble vitamin occuring naturally in plants
• It is essential for the formation of clotting factors:
II, VII, IX and X
• Natural vitamin K (phytomenadione) may be given
orally or by i.v. injection. If given p.o., it requires
bile salts for absorption
Clinical use of Vit K
Thrombosis
• Treatment and/or prevention of bleeding:
- Resulting from use of oral anticoagulant drugs
(warfarin)
- Babies: to prevent haemorrhagic disease of the
newborn (in prophylaxis)
For vitamin K deficiencies in adults:
- Sprue, coeliac disease, steatorrhoea
- Lack of bile (obstructive jaundice)
• Thrombotic and thromboembolic disease is
common and has severe consequences
including myocardial infarction, stroke, deep
vein thrombosis and pulmonary embolus
• The main drugs used for platelet-rich „white”
thrombi are the antiplatelet drugs and
fibrinolytic drugs
• Injectable anticoagulants (heparin
and newer thrombin inhibitors)
• Oral anticoagulants (warfarin,
dicumarol)
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Anticoagulants are used:
• Deep vein thrombosis
• Extension of established deep vein thrombosis or
recurrence of pulmonary embolus
• Thrombosis and embolisation in patients with
atrial fibrilation
• Clotting in extracorporeal circulations
• Cardiac events in patients with unstable coronary
syndromes
Mechanism of action
• Heparin inhibits coagulation both in vivo and in
vitro, by activating antithrombin III
• Antithrombin III inhibits thrombin and other
serine proteases by binding to the active serine
site
• Heparin modifies this interaction by binding,
via a unique pentasaccharide sequence, to
antithrombin III, changing its conformation and
accelerating its rate of action
Injectable anticoagulants
• Heparin – was discovered in 1916
• It is not a single substance but a family of
glycosaminoglycans
• Commercial preparations are extracted from beef
lung or hog intestine
Pharmacokinetics
• Heparin is not absorbed from the gut
because of its charge and large size
• Is given i.v. or s.c.
• Heparin acts immediately following i.v.
administration, but the onset is delayed by
up to 60 minutes when it is given s.c.
• The elimination half-life is 40-90 minutes
Parameteres to monitor
• Heparin is monitored by an APTT, which is
sensitive to the inhibitory effects of heparin
on factors IIa (thrombin), Xa, and IXa
LMWH’s – are low molecular weight heparins
used increasingly in place of unfractionated
heparin
• An APTT should be measured 6 hours after a
bolus dose of heparin or after any dosage
change, then every 6 hours until a
therapeutic APTT is achieved
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• LMWH – is given s.c. and has longer elimination
half-life than unfractionated heparin
• LMWHs do not prolong the APTT; unlike
unfractionated heparin, the effect of a standard
dose is sufficiently predictable that monitoring is
not require routinely
•
•
•
•
Dalteparine
Fraxiparine
Parnaparine
Nadroparine
• They are eliminated mainly by renal excretion
Patient counseling
LMWHs are as safe and effective as
unfractioned heparin (UFH) and are
more convenient to use, since patients
can be taught to inject themselves at
home and there is generally no need for
blood tests and dose adjustment
Unwanted effects
• Haemorrhage – the main hazard, treated by
stopping therapy and, if necessary, giving
protamine sulfate (heparin antagonist)
• Thrombosis – uncommon but serious adverse
effect
• Osteoporosis – only with long term therapies
• Hypoaldosteronism
• Hypersensitivity reactions
• Strict compliance is necessary in order to ensure a
consistent level of anticoagulant
• Notify health care provider if there is an increase
in bruising, hematuria, melena, hemoptysis or any
other abnormal bleeding
• Avoid aspirin or NSAIDs
• The air bubble in the LMWH syringe should be
near the plunger prior to injection. This ensures
that all of the LMWH is expelled from the syringe
and helps to minimize the amount of bleeding
from the injection site
Oral anticoagulants
• Warfarin, dicumarol
• They resemble vitamin K in structure and act by
blocking vitamin K regeneration during the
posttranslational modification of several
endogenous clotting proteins (clotting factors: VII,
IX, and X)
• They have no direct effect on previously
synthesized factors (delay)
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Pharmacokinetics
• Warfarin is given orally and is absorbed quickly
and totally from GI tract
• It has small Vd, being strongly bound to plasma
albumin
• The peak concentration in the blood occurs within
an hour of ingestion
• Metabolised by CYP450
• Warfarin crosses the placenta and is not given in
the first months of pregnancy (teratogenic)
• The therapeutic use of warfarin requires a careful
balance between giving too little, leaving
unwanted coagulation unchecked, and giving too
much thereby causing haemorrhage
• Therapy is complicated not only because the effect
of a particular dose is only seen 2 days after giving
first dose, but also because of numerous
conditions that modify sensitivity to warfarin,
including interaction with other drugs
Increased anticoagulation
• Inhibition of warfarin clearance: disulfiram,
amiodarone, metronidazole
• Displacement of warfarin from plasma
albumin: salicylates, chloral hydrate
• Increased clearance of clotting factors: thyroid
hormones
• Unknown mechanism: erythromycin, anabolic
steroids
Decreased anticoagulation
• Increased warfarin metabolism by CYP450:
barbiturates, carbamazepine, griseofulvin,
rifampin
• Reduced warfarin absorption: cholestyramine
• Unknown mechanism: penicillins
Functional synergism
• Inhibition of coagulation: heparin,
thrombolytic agents
• Inhibition of platelet function: aspirin,
NSAIDs, ticlopidine
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• The effect of warfarin is monitored by measuring
PT (prothrombin time), which is expressed as an
International Normalised Ratio (INR)
• The dose of warfarin is usually adjusted to give
INR of 2-4, the precise target depending on the
clinical situation
Unwanted effects
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•
•
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Haemorrhage (into bowel and brain)
Hepatotoxicity – uncommon
Teratogenic effects (all agents)
Necrosis of soft tissues (breast)
• For several cases treatment is long term
Platelet function
• Healthy vascular endothelium prevents platelet
adhesion
• Platelets adhere to diseased or damaged areas
and become activated – they change shape,
exposing neatively charged PL and glycoprotein
(GP) IIb/IIIa receptors, and synthesise and
release various mediators (TXA, ADP) which
stimulate other platelets to aggregate
• Aggregation entails fibrinogen binding to GP
IIb/IIIa receptors on adjacent platelets
• Activated platelets constitute the focus for fibrin
formation
• Chemotactic factors and growth factors necessary
for repair, but also implicated in atherogenesis, are
released during platelet activation
Antiplatelet drugs
ASPIRIN
• Platelets play critical role in thromboembolic
disease
• Alters the balance between TXA2, which promotes
aggregation, and PGI2 which inhibits it.
• Aspirin inactivates COX-1
• This reduces both TXA2 and PGI2 synthesis in
endothelium
• After administration of aspirin, TXA2 synthesis
does not recover until the affected cohort of
platelets is replaced in 7-10 days
• The main drug is aspirin
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Primary mechanism of action
• Inhibition of arachidonate cyclooxygenase and thus inhibition of
the production of prostaglandins and thromboxanes
• Higher doses are needed to inhibit COX in vascular
endothelium than in platelets especially when
administered p.o.
• This is because platelets are exposed to aspirin in
the portal blood, whereas systemic vasculature is
partly protected by presystemic metabolism of
aspirin to salicylate by esterases in the liver
Unwanted effects of aspirin
Consequently, low doses of aspirin
given intermittently decrease the
synthesis of TXA2 without reducing
PGI2 synthesis
• With therapeutic doses: some gastric bleeding, usually
minimal, is common
• With large doses: dizziness, deafness and tinnitus
(„salicylism”); compensated respiratory alkalosis may
occur
• With toxic doses: uncompensated respiratory acidosis
plus metabolic acidosis, the latter seen particularly in
children
• Aspirin is epidemiological linked with an encephalitis
(Reye’s syndrome) if given to children with viral infection
Dipyridamole
• PDE inhibitor
• Used in patients with a history of ischaemic
stroke or transient cerebral ischaemic attack
• Headache as the commonest side effect
Ticlopidine
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Thienopyridine derivative
It Inhibits ADP-dependent aggregation
Slow in onset, active metabolite
Severe blood dyscrasias (idiosyncratic effect)
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Clopidogrel
• Related to ticlopidine with the same
mechanism
• More effective in reducing consequences of
myocardial infarction
GP IIb/ IIIa inhibitors
• Abciximab – hybrid (murine/human)
monoclonal antibody Fab fragment directed
against GP receptor, and is used in high-risk
patients undergoing coronary angioplasty, as
an adjunct to heparin and aspirin
Clinical uses of antiplatelet drugs
• Tirofiban and eptafibatide are cyclic peptides
based on the Arg-Gly-Asp sequence that is
common to ligands for GP IIb/IIIa receptors
• Given i.v. these agents reduce early events in
unstable coronary syndrome patients treated
invasively
• Acute myocardial infarction
• High risk of myocardial infarction (patients who
have recovered from MI and patients with
symptoms from atherosclerosis, including angina
• Coronary bypass grafting
• Following PTCA
• Atrial fibrilation if oral anticoagulant is
contraindicated
Fibrinolysis (thrombolysis)
When the coagulation system is activated,
the fibrinolytic system is also set in
motion via several endogenous
plasminogen activators, including tPA,
urokinase-type plasminogen activator
(uPA), kalikrein and neutrophil elastase
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Fibrinolytic drugs
• Streptokinase (Steptase) – is a protein
extracted from cultures of streptococci. It
activates plasminogen, given i.v. Reduces
mortality in acute myocardial infarction (with
aspirin)
• At least 1 year must elapse before it is used
again
• Allergy reactions
• Alteplase, Dalteplase and Tenecteplase are
recombinant tPA
• They are more active on fibrin-bound plasminogen
than on plasma plasminogen and are therefore
said to be clot-selective
• Recombinant tPA is not antigenic and can be used
in patients likely to have antibodies to
streptokinase
• Because of their short half-lives, they must be
given in infusions
• Reteplase – long half-life (bolus)
Contraindications to thrombolytic
therapy
• Surgery within 10 days, including organ
biopsy, puncture of vessels
• Serious GI bleeding within 3 months
• History of hypertension
• Active bleeding or haemorrhagic disorder
Anistreplase
• Anisoylated plasminogen streptokinase activator
complex; APSAC
• Complex of purified human plasminogen and
bacterial streptokinase that has been acetylated to
protect the enzyme’s active site
• Rapid intravenous injection
Clinical uses
• The main use is acute myocardial infarction, within
12 hours of onset (the earlier the better!)
• Acute thrombotic stroke within 3 hours of onset
(tPA)
• Clearing thrombosed shunts and cannulae
• Acute arterial thromboembolism
Side effects
• Bleeding – the main hazard (internal)
• Allergic reactions (streptokinase)
• Hypotension (streptokinase)
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Antifibrinolytic drugs
Haemostatic drugs
Aminocaproic acid
• AMICAR
• Lysine analog that binds to lysine binding sites on
plasminogen and plasmin thus blocking the
binding of plasmin to target fibrin
• Tranexamic acid inhibits plasminogen activation
and thus prevents fibrinolysis
• It can be given orally or by intravenous injection
• It is used to treat various conditions in which there
is bleeding, such as haemorrhage following
prostatectomy or dental extraction
• In menorrhagia and for life-threatening bleeding
following thrombolytic drug administration
Aprotinin
• Inhibits proteolytic enzymes and is used for
hyperplasminaemia caused by fibrinolytic
drug overdose and in patients at risk of major
blood loss during cardiac surgery
• It is given orally and well absorbed
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