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Clinical pharmacology

Blood coagulation
&
Anticoagulants

.
Contents
• Blood coagulation
• Anticoagulants
• Classes of Anticoagulants
• Uses of anticoagulants
• Indirect-acting
• Direct-acting
• Surgery in patients receiving anticoagulant
therapy
• The use of anticoagulants in pregnancy
Blood coagulation
Blood coagulation means the
conversion of fluid blood to a solid
gel or clot. The main event is the
conversion of soluble fibrinogen to
insoluble strands of fibrin by
thrombin ,which is the last step in a
complex enzyme cascade.
Coagulation Cascade
Intrinsic Pathway Extrinsic Pathway
(vessel wall damage) (damaged tissue )

XIIa12
VIIa7
XIa11 tissuethrom
boplastin Heparin / LMWH
IXa9

Xa & V

Prothrombin Thrombin (IIa)

Thrombin-Fibrin
Clot
Anticoagulants
An anticoagulant is a substance that
prevents coagulation. Anticoagulants
can be used in vivo as a medication
for thrombotic disorders. Some
chemical compounds ( e.g. EDTA )are
used in medical equipment, such as
test tubes, blood transfusion bags,
and renal dialysis equipment.
Classes of Anticoagulants

• Indirect-acting: the coumarin


derevatives drugs (e.g. warfarin)
take about 72 h to become fully
effective, act for several days, are
given orally or by injec..
• Direct-acting: heparin and LMW
heparin are rapidly effective, and
available parenterally.
Uses of anticoagulants
Generally, these anticoagulants are
used to treat patients with
1-deep-vein thrombosis (DVT)
2- pulmonary embolism (PE)
3- atrial fibrillation (AF)
4-and mechanical prosthetic heart
valves.
Indirect-acting
Warfarin is a synthetic derivative of
coumarin, it is a Vitamin K
antagonists. it is readily absorbed
from the GIT and more than 90%
bound to plasma protein.
Mechanism of action
It is structurlly similar to vit K &
competitively inhibit epoxide
reductase that is responsible for the
reactivation of vit K to form
coagulant factors(2,7,9,10 &
anticoagulant protein c & s).
**Vit K interfere with the carboxylation of
glutamic acid residues in clotting factors II,
VII, IX and X..
Mechanism of action

In active factors 2,7,9,10,& protein c & s. Activated clotting factors

Reduced Vitamin K Oxidized Vitamin K

NAD epoxide NADH


reductase

Warfarin
Onset of action of warfarin
The effect takes several days to
develop because of the time taken
for degradation of preformed
carboxylated clotting factors.
The onset of action thus depends on
the elimination half-lives of the
relevant factors. Factor VII, with a
half-life of 6 hours, is affected first,
then IX, X and II, with half-lives of 24,
40 and 60 hours, respectively
Dose of warfarin
There is much inter-individual variation in
dose
requirements. The usual dose to initiate
therapy is 5-10 mg daily for 2 days, with the
maintenance dose then adjusted according
to
the INR.
• 1. INR 2.0-2.5 Prophylaxis of deep vein
thrombosis
• 2. INR 2.0-3.0 treatment of DVT &
pulmonary embolism.
• 3. INR 3.0-4.5 recurrent DVT &
pulmonary embolism .
MONITORING OF ANTICOAGULANT
THERAPY
MONITORING OF ANTICOAGULANT
THERAPY by INR ( international
normalized ratio ), which is the ratio
of prothrombin time in the patient to
that in a normal (un-anticoagulated)
person.
Adverse effects of warfarin
1. Bleeding (4-8%).

2. Cutaneous reactions: apart from purpura


and ecchymoses, in those who are
excessively anticoagulated; & skin
necrosis due to a mixture of
haemorrhage and thrombosis occurs
rarely where induction of warfarin
therapy is abrupt and/or the patient has
a genetically detemined deficiency of the
anticoagulant protein c & s .
Adverse effects of warfarin …
cont.

3. Warfarin used in early pregnancy


may injure the fetus (other than by
*bleeding). It causes *skeletal
disorder (5%) (bossed forehead,
sunken nose) and *absence of the
spleen.
*CNS abnormalities are reported
with warfarin used at any stage of
pregnancy and are presumed to be
due to intracranial hemorrhage.
Adverse effects of warfarin …cont.

4. Another rare complication that


may occur early during warfarin
treatment (usually within 3 to 8
weeks) is purple toe syndrome. This
condition is thought to result from
small deposits of cholesterol
breaking and flowing into the blood
vessels in the skin of the feet, which
causes a blueish purple color and
may be painful.
Management of bleeding caused
by warfarin

• Blood replacement, prothrombin


complex concentrate(containing
factor II, IX9 and X, and given i.v. as
50 units per kg of factor IX) or fresh
frozen plasma. If full reversal of
anticoagulation is judged necessary,
5 mg of Vit. K is then given by slow
i.v. injection.
Management of bleeding caused by warfarin….CONT.

• for lesser bleeding, warfarin should


be withheld and 0.5-2 mg of Vit.K
may be given by slow i.v. injection.
• INR> 7 but with out bleeding. Correct
by withholding warfarin, and given
0.5 mg OF Vit.K by slow i.v. injection
if judged appropriate.
• INR 4.5-7.0 manage by with holding
warfarin for 1-2 days and then
reviewing the INR.
Drug Interactions
Increase risk of hemorrhage:
1- Decrease metabolism by amidarone ,
metronidazole , ciprofloxacin, erythromicine ,
cimetidine , INH & flouxitine .
2- Displacement from protein binding sites caused
by loop diuretics and valproate.
3- Relative deficiency of vit K.
4-Excessive use of alcohol is also known to affect
the metabolism of warfarin
5- Low concentration of coagulation factors as in
-Hepatic failure -Hyperthyroidism
-Congestive heart failure
Drug Interactions
*Decrease anticoagulant effect
1- Decrease absorption by
cholystiramine in GIT.
2- Increase metabolism by barbiturate,
carbamazepine, rifampicin.
3- There is a decreased response to
warfarin in conditions (e.g.
pregnancy) where there is
increased coagulation factor
synthesis. Similarly, the effect of
oral anticoagulants is lessened in
Direct-Acting
Anticoagulants: Heparin
Heparin isa naturally-occurring
anticoagulant produced by basophils
and mast cells. It is highly-sulfated
glycosaminoglycan & can be used as
an injectable anticoagulant. Heparin
depends for its action on the
presence of plasma protein,
antithrombin III, which a naturally
occurring inhibitor of thrombin and of
activated factor X (Xa). in the
MONITORING OF
ANTICOAGULANT THERAPY
• The activated partial thromboplastin
time (APTT) used for detecting
abnormalities in blood clotting, and
to monitor the treatment effects with
heparin. indicator measuring the
efficacy of the "intrinsic“ pathway.
Adverse affects of heparin
1. Bleeding
2. The syndrome of thrombocytopenia (HIT
syndrome) with arterial thromboemboli
and hemorrhage which occurs in about 2-
3٪ of patients who receive heparin for a
week or more.
3. Warfarin should be substituted, if the
platelet count falls when a patient
receives heparin.
4. Osteoporosis.
5. Hypersensivity reactions and skin
necrosis may occur but are rare.
Adverse affects of heparin…cont.

6. The other complication is


hyperkalemia, which occurs in 5 to
10% of patients receiving heparin,
and is the result of heparin-induced
aldosterone suppression.
LMW heparins
• Are as effective and safe as conventional
(unfractionated) heparin at preventing
venous thrombosis.but They are
eliminated mainly by renal excretion, and
unfractionated heparin is preferred in
renal failure.
e.g. :
- Dalteparin .
- Dnoxaparin.
- demiparin.
LMW heparins …cont

Low-molecular-weight heparins are


given subcutaneously. They have a
longer half-life than unfractionated
heparin, so the effects are more
predictable and dosing less frequent
(once or twice a day). LMWHs do not
prolong the APTT; unlike
unfractionated heparin, the effect of
a standard dose is sufficiently
predictable that monitoring is not
Heparin
LMWHs
• 15 - 100 • 4 - 40
monosaccharides per monosaccharides per
molecule molecule
• High affinity for • Low affinity for plasma
plasma proteins proteins
• 30% bio-availability • 90% bio-availability
after subcutaneous after subcutaneous
injection injection
Surgery in patients receiving
anticoagulant therapy
For elective surgery warfarin may be
withdrawn about 5 days before the
operation and resumed about 3 days after
if condition seems appropriate, low-dose
heparin may be used in the intervening
period. In patients with mechanical
prosthetic valves, heparin is substituted at
full dosage 4 days before surgery and
restarted 12-14h after the operation.
Warfarin is restarted when the patient
resumes oral intake.
The use of anticoagulants in
pregnancy
Women on long term warfarin should be
advised not to become pregnant while
taking the drug.
Heparin should be substituted prior to
conception and continued through the first
trimester, after which warfarin should
replace heparin, as continued exposure to
heparin may cause osteoporosis. Warfarin
should be discontinued near term as it
exacerbates neonatal
hypoprothrombinaemia .