3. These are drugs used to reduce the
coagulability of blood.
4. Used in vivo:
1. Parenteral anticoagulants:
– Indirect thrombin inhibitors: Heparin, Low molecular weight
heparin, Fondaparinux, Danaparoid
– Direct thrombin inhibitors: Lepirudin, Bivalirudin
2. Oral anticoagulants:
– Coumarin Derivative: Bishydroxycoumarin (dicumarol),
Warfarin sodium, Acenocoumarol
– Inandione derivatives: Phenindione
– Direct factor Xa inhibitors: Rivaroxaban
5. Used in vitro:
Heparin: (150 U in 100 ml of blood)
Calcium complexing agents: Sodium citrate 1.65
gm for 350 ml of blood – acid citrate dextrose
solution – 75 ml in one unit of blood
For investigation: Sodium oxalate (10 mg for 1
ml blood and Sodium edetate – 2 mg for 1 ml of
blood)
6. Endogenous - strongest organic acid present
in the Body
Present in mast cells (MW – 75,000) – lungs,
liver and intestinal mucosa
Commercially - from Ox lung and Pig
mucosa (slaughter house)
Chemically, non-uniform mixture of straight
chain mucopolysaccharides with MW 10,000 to
20,000
Carries strong electro-negative charges
7. Types - (i) Regular or unfractionated (UFH)
Heparin (MW 5000 to 30,000) – IV or SC and (ii)
LMWH (MW 2000 to 6000) – mostly SC
8. Indirect acting - Activates plasma antithrombin III (AT
III)
Heparin-AT III complex inactivates clotting factors -
Xa, IIa, IXa, XIIa and XIIIa, but not VIIa (extrinsic
pathway)
At low conc. Xa mediated conversion of Prothrombin to
thrombin affected
Overall, Xa and IIa mediated conversion of fibrinogen to
fibrin
9. AT III (suicide inhibitor) – binds to clotting factors
slowly to form stable complex. Heparin enhances it
by
1.Heaprin creates scaffolding to bind each
(clotting factors) other with AT III
2.A specific polysaccharide in heparin binds
to AT III and induce conformational changes
– bind factors
10. Inhibition of Xa needs only the 2nd mechanism
(LMWH) - fondaparinuxs
IIa needs both the mechanism
Antiplatelet action: High doses prevents platelet
aggregation prolongs Bleeding time
Lipaemic clearing
11. Pharmacokinetics:
Highly ionized, not absorbed orally – given IV (instant
action) and SC (slow action)
Does no cross BBB and placenta
100 U/kg dose half life is 1 Hr., but above this dose 1 – 4
Hrs
Should not with – Penicillin, hydrocortisone or
tetracycline
12. Adverse effects:
1. Bleeding due to overdose – haematuria is
1st sign
2. Thrombocytopenia – aggregation of
platelets
3. Hypersensitivity – urticaria, rigor, fever
and anaphylaxis etc.
4. Alopecia and osteoporosis
13. Contraindications: Bleeding disorders,
Severe hypertension, GIT ulcer, Piles,
SABE & malignancy, Ocular &
neurosurgery, Chronic alcoholism,
cirrhosis etc.
Aspirin and antiplatelet drugs - caution
14. MW : 2000 to 6000
MOA: Acts only by interfering with Xa – inducing
conformational change in AT III – smaller effect on aPTT –
whole blood clotting time
Lesser antipatelet action and lower incidence of haemorrhagic
complications
Better Bioavailability on SC administration (once daily dosing)
Better half life (4-6 Hrs)
Laboratory monitoring not needed (aPTT and clotting time
affected little)
15. Uses: (1) Prophylaxis of DVT and
Pulmonary embolism in Surgery, stroke
and immobilized patients (2) DVT (3) UA
and MI (4) RHD and AF (5) Haemodialysis
patients
16. Unitage: Expressed in units as it is standardized
by bioassay – variable molecular size
1 mg = 120-140 U activity
Administered as IV bolus 5000-10,000 u followed
by 1000 u /hr IV drip – adjusted with aPTT value
Pretreatment aPTT value and followed by 1.5 to 2.5
times during therapy
17. Alternate: 10,000-20,000 deep SC every 8
Hrly (fine needle)
Or, Low dose SC – 5000 SC 8-12 Hry before
and after surgery to prevent DVT
Protamine Sulfate: Heparin antagonist –
given IV (1mg = 100U) – cardiac and
vascular surgery
18. In vivo not in vitro
MOA: Competitive antagonist of Vit.K – lowers the plasma
level of vit. K dependent clotting factors
Inhibits VKOR needed to generate active Vit.K
Synthesis of clotting factors diminishes within few hours-
at different times by diff. factors
But anticoagulant action starts in 1-3 days only
Commercially, mixture of R and S enantiomers
19. Kinetics: Completely absorbed from
intestine and 99% plasma protein
bound – only 1% free (many drugs can
displace (sulfonamides, phenytoin –
toxicity) – half life 36 hrs.
Dosing: Risky – calculate risk-benefit
ratio
Dose is individualized by repeated
measurement of PT
20. Optimum ratio of PT: 2-2.5 in prophylaxis
of DVT, 2-3 in DVT treatment and 3-3.5 in
MI etc.
Uses: DVT, Pulmonary embolism and
atrial fibrillation (drug of choice – 3-
4wks before and after conversion)
21. ADRs: Bleeding – epistaxis, haematuria,
bleeding GIT Intracranial haemorrhage
Minor bleeding – Vit K (takes long)
Fresh blood transfusion or blood factors
Other ADRs: Alopecia, dermatitis and
diarrhoea etc.
22. Contraindications: Same as heparin
Foetal warfarin syndrome: skeletal
abnormality – hypoplasia of nose, eye
socket, hand bones and growth retardation
25. The anticoagulant drugs either inhibit the
action of the coagulation factors (the
thrombin inhibitors, such as heparin and
heparin-related agents) or interfere with
the synthesis of the coagulation factors
(the vitamin K antagonists, such as
warfarin).
26. The fibrinolytic system dissolves
intravascular clots as a result of the
action of plasmin, an enzyme that digests
fibrin.
Plasminogen, an inactive precursor, is
converted to plasmin by cleavage of a
single peptide bond.
27. Treatment and Prevention of Deep Venous
Thrombosis
Pulmonary Emboli
Prevention of stroke in patients with
atrial fibrillation, artificial heart valves,
cardiac thrombus.
Ischaemic heart disease
During procedures such as cardiac
catheterisation and apheresis.
28. SOURCE :
Heparin is commonly extracted from
porcine intestinal mucosa or bovine lung.
Despite the heterogeneity in composition
among different commercial preparations
of heparin, their biological activities are
similar (~150 USP units/mg).
29. The USP unit is the quantity of heparin
that prevents 1 mL of citrated sheep
plasma from clotting for 1 hour after the
addition of 0.2 mL of 1% CaCl2.
30. Low-molecular-weight heparins (~ 4500
Da, or 15 monosaccharide units) are
isolated from standard heparin by gel
filtration chromatography, precipitation
with ethanol, or partial depolymerization
with nitrous acid and other chemical or
enzymatic reagents.
31. Low-molecular-weight heparins differ
from standard heparin and from each
other in their pharmacokinetic properties
and mechanism of action
32. Heparin catalyzes the inhibition of several
coagulation proteases by antithrombin, a
glycosylated, single-chain polypeptide
33. Antithrombin is synthesized in the liver
and circulates in plasma inhibition occurs
when the protease attacks a specific Arg-
Ser peptide bond in the reactive site of
antithrombin and becomes trapped as a
stable 1:1 complex.
34. Heparin increases the rate of the thrombin-
antithrombin reaction at least 1000-fold by
serving as a catalytic template to which both the
inhibitor and the protease bind. Binding of
heparin also induces a conformational change in
antithrombin that makes the reactive site more
accessible to the protease. Once thrombin has
become bound to antithrombin, the heparin
molecule is released from the complex.
35. Bleeding Bleeding is the primary
untoward effect of heparin. the effect
of heparin can be reversed quickly by the
slow intravenous infusion of protamine
sulfate, a mixture of basic polypeptides
that bind tightly to heparin and thereby
neutralize its anticoagulant effect. ~1 mg
of protamine for every 100 units of
heparin
36. The oral anticoagulants are antagonists of
vitamin K . Coagulation factors II, VII, IX,
and X and the anticoagulant proteins C
and S are synthesized mainly in the liver
and are biologically inactive unless 9–13
of the amino-terminal glutamate residues
are carboxylated to form the Ca2+-
binding g-carboxyglutamate (Gla)
residues
