pharmacology

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

23.  Factors enhancing warfarin effect: (1)
Debility, malnutrition etc. (2) Liver
diseases, chronic alcoholism (3) Newborn
(4) prolonged antibiotic therapy
 Factors decreasing warfarin effect:
Pregnancy, Nephrotic syndrome and
genetic warfarin resistance

24.  Drugs enhancing anticoagulant action: Broad
spectrum antibiotics, Aspirin (platelet
aggregation inhibition and hypoprothobinemic
action), Newer cephalosporins
(hypoprothobinemic; Chloramphenicol,
allopurinol, tolbutamide and phenytoin (inhibits
metabolism)
 Drugs reducing effect: Barbiturates,
carbamazepine, OCP and Rifampicin

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