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ANTICOAGULANT
BY :DR ISRAA OMAR
Definition of Anticoagulation
• Therapeutic interference ("blood-thinning")
with the clotting mechanism of the blood to
prevent or treat thrombosis and embolism.
Indications of Anticoagulant Therapy
• Treatment and Prevention of Deep Venous
Thrombosis
• Pulmonary Emboli
• Prevention of stroke in patients with atrial
fibrillation, artificial heart valves, cardiac thrombus.
• During procedures such as cardiac catheterisation
Enhances
Antithrombin Activity
Standard Heparin
•
•
•
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Heterogeneous mixture of polysaccharide chains
MW 3k to 30k
Active in vitro and in vivo
Administration - parenteral- Do not inject IM - only IV
or deep s.c.
• Half-life 1 - 2 hrs - monitor APTT
• Adverse effect - haemorrhage –
• antidote - protamine sulphate
Heparin mechanism of action
Heparin
Antithrombin III
Thrombin
Monitoring Heparin
• Activated Partial Thromboplastin Time (APTT)
• Normal range: 25-40 seconds
• Therapeutic Range: 55-70 seconds
Low Molecular Weight Heparin
• Changed management of venous
thromboembolism
• Standard (Unfractionated) heparin 30k
• LMWH contains polysaccharide chains MW 5k
• Enriched with short chains with higher antiXa:IIa ratio
Differences in Mechanism of Action
• Any size of heparin chain can inhibit the action of
factor Xa by binding to antithrombin (AT)
• In contrast, in order to inactivate thrombin (IIa), the
heparin molecule must be long enough to bind both
antithrombin and thrombin
• the chains of LMWH are not long enough to bind
antithrombin and thrombin
Complications of Heparin
• Hemorrhage(can be reversed by using
protamine sulfate as an antidote)
• Heparin-induced thrombocytopenia (HIT) and
thrombosis
• Osteoporosis (long-term only)more than 6
month ;the explanation of this side effect is
unknown
• Hyperkalemia
• Hypersensitivity reaction
Heparin-Induced Thrombocytopaenia
• Most significant adverse effect of heparin
after haemorrhage
• Most common drug-induced
thrombocytopenia
Treatment of HIT
• Discontinue all heparin
• If need to continue anti-coagulation, use
danaparoid (orgaran).
• Avoid platelet transfusions
• Thrombosis: use danaparoid or thrombin
inhibitor(Hirudin)
Other Parenteral Anticoagulants
DIRECT THROMBIN INHIBITORS
Drugs
• Lepirudin, desirudin, and bivalirudin, are modified
forms of hirudin, the thrombin inhibitor present in the
leech saliva.
Mechanism of action
• These drugs bind to the active site of thrombin so
preventing its coagulant activity.
Adverse effects
• Bleeding (no antidote is available)
• Antibody formation (50% of patient receiving lepirudin):
since the drug antibody complex retains anticoagulant
activity, the duration of action can be increased.
Therapeutic uses
• As an alternative to heparin when heparin is
contraindicated (patients at risk of heparin-induced
thrombocytopenia, etc.).
Other Parenteral Anticoagulants
Drotrecogin alpha
The drug is a recombinant form of activated Protein C.
Mechanism of action
• Inhibition of coagulation by proteolytic inactivation of
factor Va and VIIIa.
Adverse effects
• Bleeding (no antidote is available)
Therapeutic uses
• Given by IV infusion to patients with disseminate
intravascular coagulation due to severe sepsis (the
sepsis impairs the activation of protein C).
• In this disease the drug leads to an absolute reduction
of 6% in mortality.
Oral anticoagulant
• Warfarin is an oral anticoagulant that prevent thrombosis.
Chemistry
• Small, lipid soluble vit K analogs.
• Warfarin is the only member of this group currently used
in therapy.
Mechanism of action
• Vitamin K is an essential cofactor for the synthesis of
coagulation factors in the liver.
• Vit K quinone is the active form.
• Oxidation of this quinone to Vit K epoxide is coupled
with carboxylation of coagulation factors II, VII, IX and X,
as well as the anticoagulant factors proteins C and S.
• Epoxide is then reconverted to quinone by Vitamin K
epoxide reductase (VKOR). Warfarin blocks this
reductive conversion and the carboxylation blockade
results in incomplete molecules that are inactive in
coagulation.
Vitamin K-Dependent Clotting Factors
Vitamin K
VII
IX
X
II
Synthesis of
Functional
Coagulation
Factors
Warfarin Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
Synthesis of Non
Functional
Coagulation
Factors
Warfarin
After Warfarin Administration
• Warfarin action occurs only in vivo (in the liver)
• Warfarin has no effect on the activity on the clotting
factors that are already formed.
• Therefore the onset of warfarin activity depends upon
the rate of metabolism of these performed factors.
• Their half lives are:
• Factor II: 60 hrs
• Factor VII: 8 hrs
• Factor IX: 24 hrs
• Factor X: 40 hrs
• Protein C: 14 hrs
• Therefore there is 3-5 day delay between the drug
administration and the start of anticoagulant effect.
• Transient protein C deficiency can also be induced
because protein C and factor VII have the shortest
half-lives of the coagulation factors.
• Consequently protein C is inactivated whereas the
intrinsic system remains active for a few days. This
can cause transient hypercoagulability and local
thrombosis.
Side effects of warfarin
• Bleeding
• Hepatotoxicity
• Warfarin induced skin necrosis (can be reduced
by starting heparin and warfarin concomitantly)
Warfarin: Major Adverse Effect—
Haemorrhage
• Factors that may influence bleeding risk:
– Intensity of anticoagulation
– Concomitant clinical disorders (liver disease ,thyrotoxicosis
and fever )
– Concomitant use of other medications
1. Cimetidine and other enzyme inhibitors increase its action
while rifampicin and other enzyme inducers inhibit the
action of warfarin
2. aspirin increase its bleeding risk by working in synergistic
fashion(PLATELETS INHIBITION) .
3. NSAIDS and chloral hydrate displace it from binding sites
4. Antibiotic eliminate the intestinal flora that produce
vitamin k this will increase the risk of bleeding
– Quality of management
Prothrombin Time (PT)
• Historically, a most reliable and “relied upon”
clinical test
However:
– Proliferation of thromboplastin reagents
with widely varying sensitivities to reduced
levels of vitamin K-dependent clotting
factors has occurred
– Problem addressed by use of INR
(International Normalized Ratio)
Changing over from Heparin to
Warfarin
• May begin concomitantly with heparin therapy
• Heparin should be continued for a minimum of
four days
– Time to peak antithrombotic effect of
warfarin is delayed 96 hours (despite INR)
• When INR reaches desired therapeutic range,
discontinue heparin (after a minimum of four
days)
Warfarin: Dosing & Monitoring
• Start low
– Initiate 5 mg daily
– Educate patient
• Stabilize
– Titrate to appropriate INR
– Monitor INR frequently (daily then weekly)
• Adjust as necessary
• Monitor INR regularly (every 1–4 weeks) and
adjust
Contraindications to Warfarin Therapy
• Pregnancy (it is a erotogenic drug can cause maxillofacial
abnormality if given in the first trimester and increase
the incidence of bleeding in the new born baby in the
last trimester ;but it can be given in the middle trimester
of pregnancy but with higher doses to achieve the target
INR because there is hyper-coaguability state during
pregnancy
• Situations where the risk of hemorrhage is greater than
the potential clinical benefits of therapy
– Uncontrolled alcohol/drug abuse
– Unsupervised dementia/psychosis
Signs of Warfarin Overdosage
• Any unusual bleeding:
– Blood in stools or urine
– Excessive menstrual bleeding
– Bruising
– Excessive nose bleeds/bleeding gums
– Persistent oozing from superficial injuries
– Bleeding from tumor, ulcer, or other lesion
Reversing action of warfarin
• Plasma (fresh frozen plasma or clotting factors)
– Rapid but short-lasting, used mainly for life
threating bleeding
• Vitamin K
– Not rapid, but lasts 1-2 weeks. Do not use if wishing
to restart warfarin within next week.
• In some cases only stopping the drug can be
enough
Good luck