Drugs acting on blood

PROF. DR. SHAH MURAD

shahmurad65@gmail.com

1
The physiological systems that control
blood fluidity are both complex and
elegant.

Blood must remain fluid within the

vasculature and yet clot quickly when
exposed to nonendothelial surfaces at
sites of vascular injury.
2
When intravascular thrombi do occur, a
system of fibrinolysis is activated to
restore fluidity.

In the normal situation, a delicate

balance prevents both thrombosis and
hemorrhage and allows physiological
fibrinolysis without excess pathological 3

fibrinogenolysis.
 ANTICOAGULANTS
Many drugs have very different
mechanisms of action, but all alter the
balance between procoagulant and
anticoagulant reactions.

With these drugs, efficacy and toxicity

are necessarily intertwined. 4
For example, the desired therapeutic
effect of anticoagulation can be offset by
the toxic effect of bleeding due to
overdosing of anticoagulant.

Similarly, overstimulation of fibrinolysis

can lead to systemic destruction of
fibrinogen and coagulation factors. 5
 Blood fluidity is controlled by
the parenteral anticoagulant heparin
and its derivatives, which stimulate a
natural inhibitor of coagulant proteases;

(2) the coumarin anticoagulants,

which block multiple steps in the
coagulation cascade;

(3) fibrinolytic agents, which lyse

pathological thrombi; and
(4) antiplatelet agents, especially aspirin
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 Heparin
is a heterogeneous mixture of sulfated
(anionic) mucopolysaccharides named
because of its initial discovery in high
concentrations in the liver.
It is prepared from porcine intestinal
mucosa and bovine lung.

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 HEPARIN
It acts indirectly to facilitate
endogenous anticoagulants,
specifically antithrombin III and
heparin cofactor II.

These molecules form stable

complexes with (and thus inactivate)
clotting factors, especially thrombin.
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Heparin is released in its active form after
inactivation of the clotting factor and thus
can interact with other molecules.

The effect is greater with low

concentrations of heparin.

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Heparin is also antithrombotic due to
binding to endothelial cell walls, thus
impairing platelet aggregation and
adhesion.

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 USES of HEPARIN
the prevention or treatment of venous or
pulmonary embolism and embolization
associated with atrial fibrillation.

It is also used as an anticoagulant for

diagnostic use and blood transfusions.

used in conjunction with blood and/or

plasma for the treatment of disseminated
intravascular coagulopathy (DIC) and
other hypercoagulable conditions. 11
 PK
Absorption and distribution of heparin are
limited by the large size and polarity of the
molecule.

Oral absorption is poor; hence, it is a parenteral

anticoagulant.

Although anticoagulant activity is first order,

half-life of the drug is dose-dependent, steady-
state concentrations are difficult to achieve,
and pharmacokinetics vary among individuals. 12
Heparin is metabolized by heparinase
in the liver and by reticuloendothelial
cells. Metabolites of heparinase
activity are excreted in the urine.

The half-life is prolonged in renal or

hepatic failure.
13
Heparin can be given IV (either
intermittently or as a constant infusion)
or SC.

Deep SC or intrafat injection prolongs

persistence of therapeutic concentrations.

Large hematomas can develop after deep

IM injection. 14
High-dose heparin therapy ( 150-250
U/kg, tid ) has been recommended for
established thromboembolism.

Lower dosages ( 75 U/kg, tid) are

indicated in the management of DIC.

15
Blood coagulation times (eg,
activated partial thromboplastin
time) should be monitored during
HEPARIN therapy.

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 Side effects and toxicities
of heparin are limited to

potential hemorrhage,

and because heparin is a foreign protein,

possible allergic reactions.

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 Contraindications
Heparin is contraindicated in
bleeding animals and in
DIC(disciminated intravas
Coagulopathy) unless replacement
blood or plasma therapy is also given

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Vitamin
differ K heparin
from antagonists ( oralinanticoagulants)
primarily their duration of
activity and magnitude of effect.

Their primary importance has been because of

their toxic rather than therapeutic effects.

Therapeutic indications include oral longterm

treatment and prevention of recurrence of
thrombotic conditions (eg, aortic or pulmonary
thromboembolism and venous thrombosis)

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 There are several groups of vitamin K
antagonists.
They interfere with the hepatic synthesis of
vitamin-K-dependent clotting factors by
blocking the reduction of vitamin K epoxide
after clotting factor synthesis, thus effectively
reducing the concentration of vitamin K.
Their anticoagulant activity (and therefore
therapeutic or toxic effect) is delayed for 8-12
hr after administration or accidental ingestion
because of the persistence of factors
synthesized before administration.
Factor VII has the shortest half-life and is the
first factor to become deficient 20
 The vitamin K antagonists
are rapidly and completely absorbed after
administration PO.
Levels peak in 1 hr.

They are almost totally protein bound in the

plasma
volume of distribution is limited to the plasma
volume.

They are metabolized by the liver to primary

metabolites and then conjugated to
glucuronides.
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They undergo an enterohepatic cycle.

A variety of factors can increase the
activity of these drugs, including
hypoproteinemia, antimicrobial therapy,
hepatic disease, hypermetabolic states,
pregnancy, and the nephrotic syndrome.
The potential for drug interactions is
significant.
Because they are highly protein bound, they
can be displaced by other drugs that are
protein bound (eg, acetylsalicylic acid and
phenylbutazone), and their anticoagulant
effects can be increased to the point of toxicity.
Drug interactions also are seen with other
antihemostatics.
22
 Warfarin sodium
is the most commonly used therapeutic
preparation.
The dosage is 0.1-0.2 mg/kg, PO

Toxicity, manifest as hemorrhage, is a major

concern with vitamin K antagonists.

Coagulation times (particularly prothrombin

time), and clinical evidence of bleeding (eg,
occult blood in feces and urine) must be
monitored carefully during warfarin therapy. 23
Fibrinolytic agents(Streptokinase and streptodornase)

increase the activity of plasmin

(fibrinolysin), the endogenous compound
that is responsible for dissolving clots.

The inactive precursor of plasmin is

plasminogen, which exists in 2 forms:
plasma soluble form and fibrin (clot)
bound form. 24
 Streptokinase and streptodornase
are synthesized by streptococci and
activate both forms of plasminogen.
They are used locally as a powder,
infusion, or irrigation in the treatment of
selected chronic wounds (eg, burns,
ulcers, chronic eczemas, ear hematomas,
otitis externa, osteomyelitis, chronic
sinusitis, or other chronic lesions) that
have not responded to other therapy.
Tissue-type plasminogen activator (tPA)
preferentially activates the fibrin-bound
form of plasminogen 25
Unlike parenterally administered streptokinase,
(tissue type plasminogen activator), tPA does
not induce a systemic proteolytic state.
Selective clot lysis occurs without increasing
circulating plasmin; thus, tPA has a lower risk
of bleeding than does parenteral streptokinase.

While tPA has been used to treat aortic

thromboembolism in (0.25-1.0 mg/kg/hr, IV,
for a total dosage of 1-10 mg/kg),
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both the risk of death due to
reperfusion (and release of toxic
metabolites) and the expense of this
genetically engineered product may
limit its use.

27
 Antithrombotic drugs (ASPIRIN)

affect platelet activity, which is normally

controlled by substances (such as
prostaglandins) generated both outside
and within the platelet.

Platelet activity can be modulated by

interacting with these substances. 28
NSAID inhibit the formation of
cyclooxygenase, the enzyme
responsible for the synthesis of
prostaglandin products from
arachidonic acid that has been
released into cells and platelets.

29
The formation of all prostaglandins is
inhibited, including that of thromboxane, a
potent platelet aggregator and
vasoconstrictor.

In addition to its inhibitory effects on

cyclooxygenase, aspirin irreversibly
acetylates thromboxane synthetase, the
specific enzyme responsible for the
synthesis of thromboxane.

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Aspirin is a potent inhibitor of
platelet activity; new platelets must
be generated before the effects of
aspirin on platelet activity disappear.

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At higher dosages, aspirin inhibits
prostacylin, a prostaglandin product that
counteracts the thrombogenic effects of
thromboxane.

Thus, the drug must be used cautiously

for antiplatelet effects.

The antiplatelet dosage for is 5-10

mg/kg, every 24-48 hr 32