Drugs acting on blood and blood forming organs

For SY B Pharm students of Pune University.

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

2. Hemostasis:isaprocesswhichcauses
bleedingtostop,meaningtokeepblood
withinadamagedbloodvessel(the
oppositeofhemostasisishemorrhage)
Clottingdisordersisatermusedto
describeagroupofconditionsinwhich
thereisanincreasedtendency,often
repeatedandoveranextendedperiodof
time,forexcessiveclotting.

3. Thrombophilia known as
hypercoagibility.Itaffectsalargenumber
ofpeoplearoundtheworld.Itaffects
approximately5%to7%oftheEuropean
population.

4. Blood coagulation
Intrinsicpathway:allfactorsneededfor
Bloodcoagulationareinplasma.Slow
processaslotmanyfactorsareneededto
beactivated.
Extrinsicpathway:alsoneedstissue
factor-thromboplastin.Occurswithin
seconds.

6. Factors opposing coagulation
Antithrombinprotein 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 post-
menopausal hormone replacement
therapy are all triggering events for DVT
in women with thrombophilia.
Factor V Leiden: hypercoagulation

9. factor V Leiden
DiscoveredinLeidencityofNeitherland
FactorVisresponsibleforactivationof
factorXandXIIwhichfurtherstimulates
thrombinformation.
Thereismutationinthegeneresponsible.
SothatPKCcouldn’tdegradefactorV.so
itisoveractivityoffactorV.

10. Anticoagulants
Used in vitro
Heparin
Ca complexing agents
Usedin vivo
Heparin: LMW heparin
Oral anticoagulants: 1. Coumarin
derivatives
2. Indandionederivatives: 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
ActivatingantithrombinIII
Bindstointrinsicclottingfactors:Xa,IIa,
IXa,XIa,XIIa,XIIIaandblockstheir
activity.
NoeffectonVIIaofextrinsicpathway.
Itinhibitsconversionprothrombinto
thrombinbyXa.
Alsoitinhibitsconversionoffibrinogento
fibrin,InactivatesIIa.

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

14. Kinetics
As it large inonizedmolecule, 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%
CaCl
2 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,incontrast,consistofonlyshort
chainsofpolysaccharide.LMWHsare
definedasheparinsaltshavinganaverage
molecularweightoflessthan8000Da.
Theseareobtainedbyvariousmethodsof
fractionationordepolymerisationof
polymericheparin.

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’kineticprofile
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
EgNadoparin, Enoxaparin, Dalteparin,
Raviparinetc.

21. Fondaparinux
It is a synthetic pentasacchride. It is an
antithrombinIII 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
Bishydroxycoumarinwasmadein1941
Warfarinwasusedasanti-cogulantInvivoonly.
TheyactbyinterferingwithsynthesisofvitK
dependentclottingfactors.
TheybehaveascompetitiveinhibitorsofvitK.
Theyinterferewithregenerationofactiveformof
vitaminK,whichisessentialforcarboxylationof
clottingfactors-VII,IX,X.
VitaminKisinvolvedinthecarboxylationof
certainglutamateresiduesinproteinstoform
gamma-carboxyglutamateresidues.
Caroboxylationenhancesbindingofclotting
factorstoCa2+leadingtocoagulation.

23. Reduced Vitamin K OxidisedVitamin K
Warfarin
NADNADH
Descarboxyfactor: VII,IX,X Carboxylatedfactor: VII,IX,X

24. Synthesisofclottingfactorsdiminisheswithin2-4
hrsofwarferinadministrationtheanticoagulant
effectsdevelopsgraduallyovernext1-3days.
Therapeuticeffectoccurswhensynthesisof
clottingfactorsisreducedby40-50%.
Pharmacokinetics:Racemicwarferinsodium:
themostpopularoralanticoagulant.
R+S,Sismorepotent,metabolizedbyoxidation.
Completelyabsorbedfromstomach.
99%isplasmabound.
Itcrossesplacentaandsecretedinmilk.

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
VitK1 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
Nephroticsyndrome: drug bound to
plasma protein is lost in urine.

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

31. Drug interactions
Enhanced anticoagulant action
1.Braodspectrum antibiotics
2.Newer cephalosporinsegmoxalactam,
cefamandole, produces
hypoprothrombinemiaby the same
mech. as warfarin.
3.Aspirin: inhibits platelet aggregation, also
displaces warfarinfrom PBS.
4.Phenylbutazone: Decreases PB of
warfarin

32. 5.Long acting sulfonamides, indomethacin,
phenytoin, probenicids: competitor for
protein binding
6.Chloramphinicol, erthromycin, cimetidine,
allopurinol, amidarone, metronidazole:
inhibits warferinmetabolism
7.Tolbutamideand phenytoin: inhibits
warferinmetabolism
8.Phenformin, anabolic steroids, quinidine,
clofiberate, potentiate warferinaction
9.Liqparaffin: reduces vitK absorption.

33. Reduced anticoagulant action
1.Barbituratesandotherhypnotics(not
BZD),rifampin,grisofulvininduce
metabolismoforalanticoagulant
2.Oralcontraceptivesincreaseslevelof
clottingfactors.

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+heparinfollowed by warfarin.
Rheumatic heart disease, auricular flutter:
Warfarin/ low dose heparin/ low does
aspirin

35. Cerebrovasculardisease: little value
Preferred in ischaemicattacks due to
emboli.
Vascular surgery, prosthetic heart valves,
retinal vessel thrombosis: anticoagulants
are given along with antiplateletdrugs for
prevention of thromboembolism.

36. Fibrinolytics
These drugs are used to lysethe clot.
Curative
Fibrin is formed
Fibrinolyticsystem get activated
t-PA activates Plasminogen---Plasminis
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
throbectomyis not possible

43. Antiplateletdrugs

45. COX inhibitor: Aspirin

46. Aspirinisindicatedasprophylaxisagainst
transientischemicattacks,myocardial
infarctionandthromboembolicdisorders.
Itisalsousedforthetreatmentofacute
coronarysyndromesandinthe
preventionofreoclusionincoronary
revascularizationprocedures.
Dose:75mgto325mg

48. Ticlopidineistheoldestthienopyridine
currentlyavailable.Itisapprovedfor
secondarypreventionofthrombotic
strokesinpatientsintolerantofaspirin
andforpreventionofstentthrombosisin
combinationwithaspirin.
Clopidogrelisapprovedforprevention
ofatheroscleroticeventsfollowingrecent
myocardialinfarction,strokeor
establishedperipheralarterialdisease.It
hasabettersafetyprofilethanticlopidine.

49. Phosphodiesteraseinhibitors
Dipyridamoleactsasvasodilatorand
antiplateletagent. Itblocks
phosphodiesteraseinplateletleadingto
increaseincAMPinplatelet.Adenosine
decreasesplateletaggregability.
Itisusedincombinationwithaspirinor
warfarinintheprophylaxisof
thromboembolicdisorders.

50. GPIIb/IIIainhibitors

51. Platelet membrane GPIIb-IIIareceptors
constitute the final common pathway of
platelet aggregation, theintegrin
GPIIb/IIIaantagonists prevent cross-
linking of platelets.
Abciximabis a human-murinemonoclonal
antibodydirected against GPIIb/IIIa,

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