For SY B Pharm students of Pune University.

1. Pharmacology of drugs acting on blood and
blood forming organs
Dr Urmila M. Aswar,
Sinhgad Institute of Pharmacy,
Narhe, Pune -41

2. 
Hemostasis: is a process which causes
bleeding to stop, meaning to keep blood
within a damaged blood vessel (the
opposite of hemostasis is hemorrhage)

Clotting disorders is a term used to
describe a group of conditions in which
there is an increased tendency, often
repeated and over an extended period of
time, for excessive clotting.

3. Thrombophilia
known
as
hypercoagibility. It affects a large number
of people around the world. It affects
approximately 5% to 7% of the European
population.

4. Blood coagulation
Intrinsic pathway : all factors needed for
Blood coagulation are in plasma. Slow
process as lot many factors are needed to
be activated.
 Extrinsic pathway: also needs tissue
factor-thromboplastin. Occurs with in
seconds.


6. Factors opposing coagulation
Antithrombin protein C,
 Antithromboplastin
 fibrinolysin


7. Thrombosis
Can be in artery or vein.
 Symptoms depend on
 Where it has formed
 Area
 Is it a emboli
 There are different terms used to further
define these thrombotic episodes, such as
deep vein thrombosis (DVT) or peripheral
vascular disease, when the clots are in the
arterial system (usually in the extremities).


8. Triggering factors
Women are more sensitive
 Pregnancy, oral contraceptives and postmenopausal hormone replacement
therapy are all triggering events for DVT
in women with thrombophilia.
 Factor V Leiden: hypercoagulation


9. factor V Leiden
Discovered in Leiden city of Neitherland
 Factor V is responsible for activation of
factor X and XII which further stimulates
thrombin formation.
 There is mutation in the gene responsible.
So that PK C couldn’t degrade factor V. so
it is over activity of factor V.


10. Anticoagulants
Used in vitro
 Heparin
 Ca complexing agents
 Used in vivo
Heparin: LMW heparin
Oral anticoagulants: 1. Coumarin
derivatives
2. Indandione derivatives: Phenindione


11. Heparin






Isolated from liver
MW 10,000-20,000
Mucopolysacchride
chain
Contains negative
charge
Present in mast cells
Present in lung, liver
and intestine
Glycosaminoglycans

12. Actions
Activating antithrombin III
 Binds to intrinsic clotting factors: Xa, IIa,
IXa, XIa, XIIa, XIIIa and blocks their
activity.
 No effect on VIIa of extrinsic pathway.
 It inhibits conversion prothrombin to
thrombin by Xa.
 Also it inhibits conversion of fibrinogen to
fibrin, Inactivates IIa.


13. Low concentration interfere with intrinsic
pathway.
 High affect both.
 It inhibits platelet aggregation
 It releases lipoprotein lipase from liver
and clears VLDL, chylomicrons and
triglycerides from plasma.


14. Kinetics
As it large inonized molecule, Not
Absorbed orally
 Does not cross BBB or placenta
 T1/2: 1 hr
 Units: 1U : the amt of heparin that will
prevent 1 ml of citrated sheep plasma
from clotting for 1 hr after addition of 1%
CaCl2 solution
 Heparin sod: 1 mg has 120-140U of
activity


15. Dosage
Given IV 5,000-10,000U adults every 4-6
hrs
 Infusion given (750-1000U) till bleeding
incidence happen.
 Children: 50-100 U/kg


16. Adverse effects
Bleeding
 Thrombocytopenia
 Alopecia (transient)
 Osteoporosis
 Hypersensitivity reactions: urticaria, fever,
anaphyllaxis


17. Contradications
Bleeding disorders
 Severe hypertension
 Ocular and neurosurgery
 Chronic alcoholics
 Aspirin and other antiplatelet drugs


18. Low-molecular-weight heparins
(LMWHs)

LMWHs, in contrast, consist of only short
chains of polysaccharide. LMWHs are
defined as heparin salts having an average
molecular weight of less than 8000 Da.
These are obtained by various methods of
fractionation or depolymerisation of
polymeric heparin.

19. LMWHs have a potency for factor Xa
activity and for anti-thrombin activity (ATIII).
 More specific in action
 Less effects on platelets
 Less hemorrhagic complications.
 Good p’kinetic profile
 BA improves.
 Longer T1/2
 Dose is given in mg and not in unit
 LAB MONITORING NOT NEEDED.


20. Uses
Pulmonary embolism
 Deep vein thrombosis
 Surgeries


Eg Nadoparin, Enoxaparin, Dalteparin,
Raviparin etc.

21. Fondaparinux
It is a synthetic pentasacchride. It is an
antithrombin III mediated selective inhibition
of factor Xa. Which further inhibits thrombin
formation.
 Administered s.c daily.
 Dose: 2.5 mg
 BA: 100%
 T1/2: 17-21 hrs
 Excreted unchanged in urine
 Lesser antiplatlet action chances of
thrombocytopenia is less.


22. Oral anticoagulants
Bishydroxycoumarin was made in 1941
Warfarin was used as anti-cogulant In vivo only.
They act by interfering with synthesis of vit K
dependent clotting factors.
 They behave as competitive inhibitors of vit K.
They interfere with regeneration of active form of
vitamin K, which is essential for carboxylation of
clotting factors- VII, IX, X.
 Vitamin K is involved in the carboxylation of
certain glutamate residues in proteins to form
gamma-carboxyglutamate residues.
 Caroboxylation enhances binding of clotting
factors to Ca2+ leading to coagulation.




23. Descarboxy factor:VII,IX,X
Carboxylated factor:VII,IX,X
Reduced Vitamin K
Oxidised Vitamin K
Warfarin
NADH
NAD

24. Synthesis of clotting factors diminishes within 2-4
hrs of warferin administration the anticoagulant
effects develops gradually over next 1-3 days.
 Therapeutic effect occurs when synthesis of
clotting factors is reduced by 40-50%.






Pharmacokinetics: Racemic warferin sodium:
the most popular oral anticoagulant.
R+S, S is more potent, metabolized by oxidation.
Completely absorbed from stomach.
99% is plasma bound.
It crosses placenta and secreted in milk.

25. Bishydroxycoumarin (Dicoumarol)
Absorbed orally
 Metabolism is dose dependent
 T1/2 is prolonged at higher doses
 Has poor GI tolerance
 Available as 50 mg tab


26. Acenocoumarol
T1/2 of 8 hrs. produces an active
metabolite.
 T1/2: 24 hrs.
 Acts rapidly


27. Adverse effects










Bleeding
Epistaxis
Hematuria
Bleeding in GIT
Internal hemorrhage
Treatment:
Stop anticoagulant
Blood transfusion
Plasma replenishment
Vit K1 administration

28. Factors enhancing effect of oral
anticoagulants
Malnutrition
 Prolonged antibiotic use
 Liver disease : low synthesis of CF
 Newborns: low CF
 Hyperthyroidism: Fast degradation of CF


29. Factors decreasing the effect of oral
anticogulants
Pregnancy
 Nephrotic syndrome: drug bound to
plasma protein is lost in urine.


30. Contraindications
Pregnancy: skeletal abnormalities, foetal
warfarin syndrome– hypoplasia of nose,
eye socket, hand bones and growth
retardation.
 If given in later stage of pregnancy, it can
cause CNS defects, foetal death.


31. Drug interactions
Enhanced anticoagulant action
1. Braod spectrum antibiotics
2. Newer cephalosporins eg moxalactam,
cefamandole, produces
hypoprothrombinemia by the same
mech. as warfarin.
3. Aspirin: inhibits platelet aggregation, also
displaces warfarin from PBS.
4. Phenylbutazone: Decreases PB of
warfarin


32. 5.
6.
7.
8.
9.
Long acting sulfonamides, indomethacin,
phenytoin, probenicids: competitor for
protein binding
Chloramphinicol, erthromycin, cimetidine,
allopurinol, amidarone, metronidazole:
inhibits warferin metabolism
Tolbutamide and phenytoin: inhibits
warferin metabolism
Phenformin, anabolic steroids, quinidine,
clofiberate, potentiate warferin action
Liq paraffin: reduces vit K absorption.

33. Reduced anticoagulant action
1.
2.
Barbiturates and other hypnotics (not
BZD), rifampin, grisofulvin induce
metabolism of oral anticoagulant
Oral contraceptives increases level of
clotting factors.

34. Uses
Deep vein thrombosis and pulmonary
embolism: venous thrombi are fibrin
thrombi- 3 month therapy
 Post stroke required prophyllaxis.
 Myocardial infarction: arterial thrombi are
platelet thrombi. Not very beneficial.
Aspirin+heparin followed by warfarin.
 Rheumatic heart disease, auricular flutter:
Warfarin/ low dose heparin/ low does
aspirin


35. Cerebrovascular disease: little value
 Preferred in ischaemic attacks due to
emboli.
 Vascular surgery, prosthetic heart valves,
retinal vessel thrombosis: anticoagulants
are given along with antiplatelet drugs for
prevention of thromboembolism.


36. Fibrinolytics
These drugs are used to lyse the clot.
 Curative
 Fibrin is formed
 Fibrinolytic system get activated
 t-PA activates Plasminogen---Plasmin is
the serine protease which digest fibrin
 Plasminogen is present in bound (fibrin)
and free form.


37. Fibrinolysis

38. Fibrinolytics
Strptokinase
 Urokinase
 Altelase


39. Streptokinase
Obtained from Streptococci C
 Activates plasminogen
 T1/2: 30-80 m
 Antigenic
 less expensive


40. Urokinase
Isolated from human urine
 Prepared from human kidney cells
 Activates plasminogen directly
 T1/2: 10-15 m
 Side effects: Less allergic
 fever


41. Alteplase
Produced by recombinant DNA tech.
 Activates plasminogen bound to fibrin.
 T1/2: 4-8 m
 Expensive


42. Uses
Acute MI
 Therapy to be initiated 12 h of symptoms
 Can be given IV
 Heparin or aspirin is started thereoff
 Deep vein thrombosis
 Pulmonary embolism
 Peripheral arterial occlusion
 To be treated with in 72 hrs advised if
throbectomy is not possible


43. Antiplatelet drugs

45. COX inhibitor: Aspirin

46. Aspirin is indicated as prophylaxis against
transient ischemic attacks, myocardial
infarction and thromboembolic disorders.
It is also used for the treatment of acute
coronary syndromes and in the
prevention of reoclusion in coronary
revascularization procedures.
 Dose: 75 mg to 325 mg


48. Ticlopidine is the oldest thienopyridine
currently available. It is approved for
secondary prevention of thrombotic
strokes in patients intolerant of aspirin
and for prevention of stent thrombosis in
combination with aspirin.
 Clopidogrel is approved for prevention
of atherosclerotic events following recent
myocardial
infarction,
stroke
or
established peripheral arterial disease. It
has a better safety profile than ticlopidine.


49. Phosphodiesterase inhibitors
Dipyridamole acts as vasodilator and
antiplatelet
agent.
It
blocks
phosphodiesterase in platelet leading to
increase in cAMP in platelet. Adenosine
decreases platelet aggregability.
It is used in combination with aspirin or
warfarin
in
the
prophylaxis
of
thromboembolic disorders.

50. GPIIb/IIIa inhibitors

51. Platelet membrane GPIIb-IIIa receptors
constitute the final common pathway of
platelet aggregation, the integrin
GPIIb/IIIa antagonists prevent crosslinking of platelets.
Abciximab is a human-murine monoclonal
antibody directed against GPIIb/IIIa,

52. UESES
CAD: MI
 Coronary bypass implant
 Prosthetic heart valves
 Venous thrombosis
 Peripheral vascular disease
