Download ADRENOCEPTOR AGONIST SYMPATHOMIMETICS

Fibrinolytics, anticoagulants
and antiplatelets
Anticoagulants
Drugs that
coagulation
anticoagulant
interfere
cascade
with
are
blood
called
COAGULATION CASCADE
Key Clotting Factor is
THROMBIN
COAGULATION CASCADE
ANTICOAGULANTS & COAGULATION CASCADE
Classification of anticoagulants
1. Parenteral anticoagulants
2. Oral anticoagulants
Parenteral Anticoagulants
(THROMBIN INHIBITORS)
 Indirect
thrombin inhibitors
 High molecular weight (HMW) heparin
or unfractionated (UFH) heparin.
 Low molecular weight (LMW) heparin.
 Direct
thrombin inhibitors
Indirect Thrombin Inhibitors
antithrombin III –dependent
thrombin inhibitors
 High molecular weight (HMW) heparin
or unfractionated (UFH) heparin.
 Low molecular weight (LMW) heparin.
 are
unfractionated (UFH) heparin.
Heterogeneous
mixture of sulfated
mucopolysaccharides (glycosaminoglycan).
 Strongly acidic nature.
Extraction of unfractionated (UFH)
heparin.
Extracted
from porcine intestinal mucosa &
bovine lung.
Mechanism of Action of UFH

Has anticoagulant effect that depends upon
antithrombin III
 Antithrombin III: is a natural anticoagulant
that inhibits activated clotting factors especially
(IIa, IXa, Xa, XIa).
 This inhibition is slow but increased 1000 fold
in presence of heparin.
Heparin  inhibits activated clotting factors
in blood by  activity of antithrombin III
against activated clotting factors as (IIa, IXa,
Xa, XIIa)  inhibits blood clotting.
 LMWH acts via increasing activity of
antithrombin III against activated clotting
factor Xa .

MECHANISM OF ACTION OF UFH
MECHANISM OF ACTION OF UFH & LMWH
Heparin
Free
Heparin
Pharmacokinetics of UFH
Given only parenerally (S.C. or I.V) Not I.M
(hematoma).
 Immediate anticoagulant effect (t ½ = 60 - 90
min).
 Metabolized in the liver (80 %) - 20 % excreted
unchanged in urine (not by microsomes).
 Does not cross placenta & not excreted in
milk.





Low Molecular Weight Heparin (LMWH)
Enoxaparin – Dalteparin -Danaproid.
prepared by chemical or enzymatic
depolymerization of UFH
LMWHs are antithrombin III-dependent
Administration: S.C. in- & out-hospital
LMW heparins
1. Increased bioavailability
2. Longer biological half life.
3. Less frequent dosing requirements
4. Doses are specified in milligrams
5. Favorable pharmacokinetic characters.
6. predictable anticoagulant effect
7. No dose adjustment or monitoring
8. Less incidence of bleeding and
thrombocytopenia.
Pharmacological Actions
1.
Heparin& LMWH have anticoagulant activity
in vivo & in vitro.
Control of Therapy
Unfractionated heparin (UFH)
1. Activated partial thromboplastin time
(aPTT) 1.5 - 2.5 times that of the normal
value (30 sec).
2. Whole blood clotting time (WBCT):
2 - 3 times the normal value (5 - 7 min).
LMWH estimation of plasma factor Xa.
Side Effects of Heparin
1.
2.
3.
4.
Bleeding
Thrombocytopenia & Thrombosis
Hypersensitivity reactions: (Antigenicity due
to animal source) rarely occurring reactions
include urticaria, rash, rhinitis.
Reversible alopecia & osteoporosis (long
term, for 6 months or longer).
Heparin-induced thrombocytopenia (HIT)



is an immune reaction that occurs in up to
3% of patients on heparin therapy for 5-14
days due to formation of IgM & IgG against
heparin-PF4 complex
Platelet count is required.
Lower risk with LMWH
Treated by
1.
2.
Heparin discontinuation
Direct thrombin inhibitor is used
Heparin antidote
Protamine sulphate



Basic peptide
Given I.V. slowly (1 mg / 100 U heparin).
Excess protamine should be avoided since
it has anticoagulant effect.
Uses of heparin
for the prevention of
1. Pulmonary embolism.
2. Deep vein thrombosis.
3. Post-operative venous thrombosis.
4. Stroke.
5. Myocardial infarction.
6. Hemodialysis.
7. Reduction of coronary artery thrombosis
after thrombolytic treatment
8. Anticoagulant of choice in pregnant women
Contraindications of heparin
1.
2.
3.
4.
5.
6.
7.
8.
9.
Hemophilia, thrombocytopenia.
Severe hypertension.
Intra cranial hemorrhage.
Threatened abortion
Ulcerative lesions of GIT.
Threatened abortion.
Advanced hepatic or renal disease.
Hypersensitivity to heparin.
Patients who have had surgery of CNS, eye
or spinal cord.
Differences
HMWH
LMWH
 activity of a
antithrombin III against
active factor II, IX, X, XI,
and XII.
 activity of
antithrombin III
against Xa
High
Low
thrombocytopenia High
Low
T½
Short
Long ( double )
Bioavailability
Low
High
Control of dose
aPTT, WBC.
Plasma factor Xa
Administration
3 - 4 dose / day
( I.V. or S.C )
1 - 2 dose / day
S.C. only
Efficacy
Equal
Equal
MW
5000 - 30.000
2000 - 9000
Bleeding
tendency
Direct Thrombin Inhibitor anticoagulants
Lepirudin-Bivalirudin
acts via direct binding to active site on
activated factor II (thrombin)
 is antithrombin III- independent.
 Prepared by recombinant DNA technology
 Given I.V.
 Has short duration of action (1 hr)
Used for treatment of thrombosis in
HIT patients.

Lepirudin
Is accumulated in renal insufficiency.
 It is monitored by aPTT
 No antagonists are available.

ORAL ANTICOAGULANTS
Coumarin anticoagulants
 e.g. warfarin

Warfarin
Mechanism of action




Warfarin is vitamin K antagonist (vitamin K epoxide
reductase inhibitor).
Reduced vitamin K is required for γ-carboxylation of
glutamate residues in clotting factors.
Warfarin acts by inhibiting the activation of several
clotting factors (II, VII, IX, X ) by blocking
γ-carboxylation of glutamate residues in clotting
factors in the liver.
This results in the production of inactive clotting
factors lacking ɣ-carboxyglutamyl residues
vitamin K reductase
The reduced vit
K is converted
into vitamin K
epoxide which
is reduced back
by vitamin K
reductase the
target enzyme
which warfarin
inhibits
Pharmacokinetics








Taken orally.
Highly bound to plasma protein (low Vd).
Long plasma half life (36 h).
Cross placenta (# pregnancy).
Metabolized in the liver by cytochrome
P450
Excreted in urine and stool.
Delayed onset of action (8-12 h).
Acts in vivo only.
Side effects
1.
2.
3.
4.
5.
slow onset of action
Hemorrhage : treated by vitamin K 1
Soft tissue necrosis
Drug interactions
Teratogenicity:
 hemorrhagic disorder
 abnormal bone formation in the fetus.
Warfarin Drug interactions
Warfarin action is increased by:
Broad spectrum antibiotics
Cyt P450 inhibitors: Cimetidine, erythromycin
Aspirin
Diseases Hyperthyroidism & liver disease
Warfarin Drug interactions
Warfarin action is decreased by
Cyt P450 inducers:
Phenobarbitone, rifampicin, phenytoin
Contraindications
Pregnancy
Hypoprothrombinemia (Liver disease).
Overdose of warfarin
Treated by vitamin K
Control of warfarin Therapy
Prothrombin time (PT)
Time required for plasma clotting with
calcium and thromboplastin (10-12
seconds) 2-4 times expressed as INR
International normalized ratio (INR)
Ratio between patients PT and standard PT
(2-4).
Uses for Maintenance of anticoagulant activity.
Uses of anticoagulants
for the prevention of
1.
2.
3.
4.
5.
Pulmonary embolism recurrence
Deep vein thrombosis
Post - operative venous thrombosis
Stroke
Myocardial infarction
6. During hemodialysis
7. Unstable angina
Heparin (LMW) for short term action
Warfarin is used for prolonged therapy
Contraindications of anticoagulants
1.
2.
3.
4.
5.
6.
7.
8.
9.
Hemophilia, thrombocytopenia.
Severe hypertension.
Intra cranial hemorrhage.
Threatened abortion
Ulcerative lesions of GIT.
Threatened abortion.
Advanced hepatic or renal disease.
Hypersensitivity to heparin.
Patients who have had surgery of CNS, eye
or spinal cord.