HAEMOSTASIS-
Cessation of blood loss from damaged blood
Vasoconstriction
Exposure to
tissues activate
Tissue factor
and initiate
coagulation
Tissue Factor
WHAT ARE PLATELETS ?
White, discoid
Smallest element of flowing blood
• 1 - 2 microns diameter
Lipid bilayer membrane
Norm...
Normal Function of Platelets
Haemostasis
Preventing
bleeding
from
wounds
Integrity
and repair
of the
vessel wall
Collagen VWF
INJURY
Platelet Adhesion
& Secretion
Platelet aggregation
Tissue Factor
Coagulation Cascade
Thrombin
Fibrin
H...
Thrombogenesis
 Platelet aggregates bound
together by fibrin strands
(white clots)
 Consist mainly of fibrin
and RBCs (r...
Platelets and Thromboemolism
 Occludes artery /
disintegrates into
emboli occluding
distal vessels resulting
in ischemic ...
Vascular Injury
 Trauma
 Surgical manipulation
 Prior thrombosis
 Atherosclerosis
Vascular
Injury
PLATELET AGGREGATORS
Collagen
Von willebrand factor
ADP
Thromboxane A2
Stress
Thrombin
Damaged blood vessel
Release of collagen Activation of platelets
Arachidonic acid Release of thrombinRelease of
ADP
Cyclic...
Targets for anti-platelet therapy
Aspirin
NSAIDs
ADP
receptor
COX-1
TXA2
GPIIb - IIIa
Signalling
pathways
ADP receptor
ant...
PGI 2- (Prostacyclins)
Naturally occurring potent vasodilator and inhibitor of platelet
aggregation.
Produced by vessel wa...
CLASSIFICATION OF
ANTIPLATELET AGENT-
1. PGI 2
2. TXA2 inhibitors-
• Ticlopidine, Clopidogrel
3. ADP antagonists-
• Dipyri...
Damaged blood vessel
Release of collagen Activation of platelets
Arachidonic acid Release of thrombinRelease of
ADP
Cyclic...
• MOA-
ASPIRIN-
In platelets major COX product is TXA2 ,
a labile inducer of platelet aggregation and
potent vasoconstrict...
For complete inactivation of platelet COX
dose of aspirin req. is 160 mg daily.
Reason—
Higher doses decrease efficacy of ...
USES OF ASPIRIN
Prevention of AMI in pts. Of unstable angina
Prevention of reinfarction in pts. Of AMI and IHD
Prevention ...
ADP antagonists- Ticlopidine
Ticlopidine blocks Gi coupled ADP receptors
It is a prodrug requires conversion to active for...
Clopidogrel
Less toxic then ticlo. less incidence of leucopenia, thrombocytopenia.
Less used than Ticlopidine
MOA, PK prof...
• MOA
Inhibition of PDE (phospodiesterase enzyme) and/ or by
blockade of adenosine which act at A2 receptor to stimulate
a...
Xanthine analogue
Increases deformability of RBCs thus increases
microcirculation, reduce fibrinogen levels, inhibit pl.
a...
Glycoprotein IIB/IIIA receptors antagonists
Platelet surface receptor, receptor for fibrinogen and von
willebrand factor,w...
Abciximab
Monoclonal antibody cause platelet receptor blockade.
Given IV max. effect seen with in 2hrs, DOA 10-12 hrs.
Use...
Questions
 Discuss in detail antiplatelet drugs. Add note on
use of low dose Aspirin as an antiplatelet agent.
 Short no...
Coagulation Phase
Two major pathways
• Intrinsic pathway
• Extrinsic pathway
13 soluble factors are involved in clotting
B...
Clotting factors
35
Intrinsic Pathway
 All clotting factors are
within the blood vessels
 Clotting slower
 Activated partial
thromboplastin...
Diagnosis of coagulation defects
• Defective Intrinsic
Pathway
Prolonged APTT
No change in PT
• Defective Extrinsic
Pathwa...
Blood Vessel Injury
IX IXa
XI XIa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin II Throm...
Activation
Inactive XI Active XIa
XIIa
+
ANTICOAGULANTS
 These are the drugs used to reduce coagulability of blood.
 Classification
In vitro anticoagulants In vi...
B) Oral anticoagulants
 Warfarin sodium
 Bishydroxycoumarin (dicumarol)
 Acenocoumarol
 Phenindione
Heparin
Chemistry & Occurence
Straight chain mucopolysaccharide,
glycosaminoglycans
MW 10000-20000. Average=15,000 d (~45m...
MOA
 Heparin binds to antithrombin III -----complex
 Increases thrombin –AT reaction 1000folds.
 Heparin induces confor...
ATIII-SUCCIDE SUBSTRATE
Thrombin inhibition catalysed by
heparin
AT
R
H
AT H
AT H
AT H
R
P
P
P
P
R
R
FXa inhibition catalysed by
heparin
AT
R
H
AT H
AT H
AT H
R
P
P
P
P
R
R
Anticoagulant Properties of Heparin
1. Inhibits the thrombin-mediated conversion of
fibrinogen to fibrin
2. Inhibits the a...
Pharmacokinetics
 Not effective orally
 Sc/ iv administration
 Onset immediate, peak in 5-10mins
 Metabolized in liver...
Unfractionated Heparin
 High Dose
 Treatment of venous/arterial thrombi
 Requires monitoring
 IV- 5,000 Units bolus, t...
Low Dose Unfractionated Heparin
 Surgical Prophylaxis
 5,000 Units SC 2 hr preop
 5,000 Units SC every 12 hours
 Medic...
ADVANTAGES OF LMWH
1. Less anti IIa activity
than anti Xa activity
2. Good pk profile
3. More predictable dose
response
4....
LMWH
 1mg/ kg S.C BD for DVT
 30mg/ Kg S.C. for DVT
prophylaxis of Knee and hip
surgery
 1mg/ kg S.C BD for DVT
 30mg/...
Adverse effects
 Allergic and anaphylactic manifestations
 Bleeding (1-33%)-antidote- Protamine sulphate
 Heparin induc...
Mechanisms of HIT
 Type 1 (Non immune):
 Fall in platelet count occurs within the first two days after
heparin initiatio...
Warfarin
Warfarin, a coumarin derivative, is the most
commonly used oral anticoagulant (OAC) .
Warfarin is a vitamin K ant...
Oral anticoagulants : warfarin, dicumarol
 Coumarins - warfarin, dicumarol
 Isolated from clover leaves
 Structurally r...
Mechanism of action
Descarboxy Prothrombin Prothrombin
Reduced Vitamin K Oxidized Vitamin K
NADHNAD
Warfarin
Warfarin Monitoring
• Why monitor? Need to balance proper
anticoagulation without bleeding risk.
• Monitored with PT, expr...
INR : International Normalized
Ratio.
 Different thromboplastins vary in sensitivity
 To give PT values a consistent bas...
Drug interaction- Prototype Warfarin
Category Mechanisms Examples of
drugs
Drugs that
Increase
Warfarin Activity
Decrease ...
New Anticoagulants
Limitations of
traditional
anticoagulants, both with
Heparin and Warfarin,
have prompted the
developmen...
New Anticoagulants
Parenteral
FXa
Inhibitors
FXa Inhibitors
Parenteral synthetic pentasaccharide
analogs
• Synthetic and highly selective
inhibitor of FXa
• Acts as co...
FXa Inhibitors
Parenteral synthetic pentasaccharide
analogs
• LMW mixture of heparinoids
(glycosaminoglycans, GAGs); acts ...
Direct Thrombin Inhibitors
• Recombinant hirudin, a
derivative of the saliva of the
medicinal leech Hirudo medicinalis
• F...
Direct Thrombin Inhibitors
• A synthetic anticoagulant for
prophylaxis or treatment of
thrombosis in patients with
heparin...
Direct Thrombin Inhibitors
• Synthetic polypeptide hirudin analog
that interacts with the thrombin
active site to reversib...
Direct Thrombin Inhibitors
• Studies have shown similar
efficacy and bleeding risk to
warfarin
• Does not need monitoring
...
The Extent of Thrombotic
Disease Annually in the U.S.
1.5 million MIs-Mortality of 30% (450,000)
500,000 CVAs -Mortality o...
Venous Thromboembolism
Third most common
cardiovascular disease
Significant morbidity and
mortality
VTE includes:
• Deep V...
Economy Class Syndrome
Medical condition called Venous
Thromboembolism
Fibrin thrombi.
3months anticoagulants theraphy is ...
Deep Vein Thrombosis
 Blood clot of lower leg or
thigh
 Approximately 1 per 1,000
people affected by DVT
 Hospitalizati...
Pulmonary Embolism
Dislodged blood clot
entering the pulmonary
circulation
Accounts for 5-10% of all
hospital deaths
80% o...
Deep Vein ThrombosisEmbolusPulmonary Embolism
AMI AND UNSTABLE
ANGINA
Arterial thrombi-platelet thrombi
Use of anticoagulants???
Beneficial in preventing mural thrombi ...
RHD, AF
Warfarin / low dose aspirin /
LMWH are effective in
preventing stroke due to
embolism from fibrillating atria.
War...
Blood Hypercoagulability
Increased procoagulants
Decrease in inhibitors
Impaired fibrinolysis
Occurs in obstretic conditio...
• Enhance degradation of clots
• Activation of endogenous
protease
• Plasminogen (inactive form) is
converted to Plasmin (...
FIBRINOLYTICS
• Streptokinase - bacterial product -
continuous use - immune reaction
• Urokinase - human tissue derived - no
immune resp...
 Streptokinase is a protein (but not an
enzyme in itself) synthesized by streptococci
that combines with the pro-activato...
 Urokinase is a human enzyme synthesized by
the kidney that directly converts plasminogen to
active plasmin.
 Plasmin fo...
 Plasminogen can also be activated endogenously
by tissue plasminogen activators (t-PAs).
 Activate plasminogen that is ...
 RETEPLASE is less expensive than Alteplase.
It lacks the major fibrin-binding domain thus is
less fibrin-specific than A...
DOSES
• Dose:250000 U loading dose
followed by 100000 U every hr for
24 -72 hrs
Streptokinase
• Loading dose of 300000 U
f...
Contraindications to Antithrombotic
Therapy
• Pre-existing coagulation or platelet
defect, thrombocytopenia, or other
blee...
Contraindications to Antithrombotic
Therapy
• Recent thoracic, abdominal, or
central nervous system surgery
• Recent cereb...
• AMI
• Multiple pulmonary emboli.
• Pulmonary embolism with
hemodynamic instability
• Central DVT
• Pheripheral vascular ...
Drug preparations : to stop
bleeding
Fibrinolytic Inhibitors:
Aminocaproic Acid
 Similar to the amino acid lysine, is a synthetic
inhibitor of fibrinolysis
 ...
USES
 Adjunctive therapy in hemophilia
 Bleeding from fibrinolytic therapy
 Prophylaxis for re-bleeding from intracrani...
Drug preparations: clotting deficiencies
Vitamin K
• Oral : 5 mg tablets
Plasma fractions - for hemophilia
• Antihemophili...
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
Antiplatelet new  and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations
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Antiplatelet new and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations

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Antiplatelet new and anti coagulants : Dr Rahul Kunkulol's Power Point Presentations

  1. 1. HAEMOSTASIS- Cessation of blood loss from damaged blood
  2. 2. Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulation Tissue Factor
  3. 3. WHAT ARE PLATELETS ? White, discoid Smallest element of flowing blood • 1 - 2 microns diameter Lipid bilayer membrane Normal range 150000 – 450000 microlitre blood Formed from cytoplasm of megakaryocytes No nucleus
  4. 4. Normal Function of Platelets Haemostasis Preventing bleeding from wounds Integrity and repair of the vessel wall
  5. 5. Collagen VWF INJURY Platelet Adhesion & Secretion Platelet aggregation Tissue Factor Coagulation Cascade Thrombin Fibrin Haemostatic plug Vaso- constriction Blood Vessel Endothelium Subendothelium
  6. 6. Thrombogenesis  Platelet aggregates bound together by fibrin strands (white clots)  Consist mainly of fibrin and RBCs (red clots) Arterial thrombus
  7. 7. Platelets and Thromboemolism  Occludes artery / disintegrates into emboli occluding distal vessels resulting in ischemic necrosis of tissue supplied by the artery.(AMI)  Veins low pressure : Reduced blood flow (stasis)  Especially in valve pockets  Causes tissue drained by the vein to be edematous and inflamed (DVT)
  8. 8. Vascular Injury  Trauma  Surgical manipulation  Prior thrombosis  Atherosclerosis Vascular Injury
  9. 9. PLATELET AGGREGATORS Collagen Von willebrand factor ADP Thromboxane A2 Stress Thrombin
  10. 10. Damaged blood vessel Release of collagen Activation of platelets Arachidonic acid Release of thrombinRelease of ADP Cyclic endperoxidase COX Release of TXA2 Activation of glycoprotein IIB/IIIA receptors Fibrinogen fibrin Activates P2Y1 Gq Gi Changes in platelet shape Increases phospoinositol inhibits adenylcyclase, decrease CAMP ?
  11. 11. Targets for anti-platelet therapy Aspirin NSAIDs ADP receptor COX-1 TXA2 GPIIb - IIIa Signalling pathways ADP receptor antagonists Clopidogrel THROMBIN receptor Thrombin inhibitors II Phosphodiesterase inhibitors dipyridamole Fibrinogen Receptor Antagonists AA
  12. 12. PGI 2- (Prostacyclins) Naturally occurring potent vasodilator and inhibitor of platelet aggregation. Produced by vessel walls, also present in brain ,gut and kidney. Formed from PG endperoxidase by the action of COX Inhibit platelet aggregation by stimulating adenylcyclase increasing cyclic AMP levels in platelets. Prostacyclins causes hypotension , tachycardia ,headache. intense facial flushing Very unstable ,1/2 life of 3 mins. Prostacyclins (Epoprostananol)-used during haemodialysis.
  13. 13. CLASSIFICATION OF ANTIPLATELET AGENT- 1. PGI 2 2. TXA2 inhibitors- • Ticlopidine, Clopidogrel 3. ADP antagonists- • Dipyridamole, Pentoxifylline 4. Phospodiesterase inhibitor- 5. Glycoprotein IIB/IIIA receptors antagonists- Abciximab, Eptifibatide, Tirofiban
  14. 14. Damaged blood vessel Release of collagen Activation of platelets Arachidonic acid Release of thrombinRelease of ADP Cyclic endperoxidase COX Release of TXA2 Activation of glycoprotein IIB/IIIA receptors Fibrinogen fibrin Activates P2Y1 Gq Gi Changes in platelet shape Increases phospoinositol inhibits adenylcyclase, decrease CAMP ?
  15. 15. • MOA- ASPIRIN- In platelets major COX product is TXA2 , a labile inducer of platelet aggregation and potent vasoconstrictor. Aspirin blocks production of TXA2 by covalently acetylating serine residue near the active site of COX, this enzyme produces cyclic endperoxidase precursor of TXA2. Since platelets do not synthesize new proteins hence the action of aspirin on platelets is permanent (7-10 days).
  16. 16. For complete inactivation of platelet COX dose of aspirin req. is 160 mg daily. Reason— Higher doses decrease efficacy of aspirin as they inhibit production of prostacyclins which is spared at low doses. (75-150mg) Higher doses also increase toxicity esp.. Bleeding.
  17. 17. USES OF ASPIRIN Prevention of AMI in pts. Of unstable angina Prevention of reinfarction in pts. Of AMI and IHD Prevention of stroke in pts. Of cerbrovascular accidents and h/o TIA For improving prognosis in patients with atherosclerotic peripheral vascular diseases Percutaneous angioplasty for coronary thrombosis , Primary prophylaxis of thromboembolism in pts with prosthetic heart valves
  18. 18. ADP antagonists- Ticlopidine Ticlopidine blocks Gi coupled ADP receptors It is a prodrug requires conversion to active form by Cyp450. Rapid absorp. ,high bioavailability Maximal inhibition of platelet inhibition it takes 8-11 days after starting therapy. Dose-loading 500mg for rapid onset of action. Usual dose 250mgBD AE- Nausea ,Vomiting, Diarrhea, Neutropenia, Thrombotic Thrombocytopenia Uses- Prevention cerebrovascular events, in 2ndary prevention of stroke Unstable angina Combination –Aspirin + ticlopidine---angioplasty, coronary artery stenting
  19. 19. Clopidogrel Less toxic then ticlo. less incidence of leucopenia, thrombocytopenia. Less used than Ticlopidine MOA, PK profile same as Ticlopidine Dose 75mg/day Rest same as Ticlopidine.
  20. 20. • MOA Inhibition of PDE (phospodiesterase enzyme) and/ or by blockade of adenosine which act at A2 receptor to stimulate adenylcyclase thus increase CAMP causing platelet inhibition. Current recommended use- Along with Warffarin in primary prophylaxis of thromboemboli in pts with prosthetic heart valves
  21. 21. Xanthine analogue Increases deformability of RBCs thus increases microcirculation, reduce fibrinogen levels, inhibit pl. aggregation. Uses- CVAs esp.TIA(transient ischemic attacks) , Ischemic ulcers of legs Dose 400mg tds
  22. 22. Glycoprotein IIB/IIIA receptors antagonists Platelet surface receptor, receptor for fibrinogen and von willebrand factor,which anchors platelets to foreign surface and each other thereby mediating aggregation. Receptor is activated by TXA2, Collagen, and thrombin to developbinding sites for its ligands. Inhibition of binding to this receptor blocks platelet aggregation induced by the agonist.
  23. 23. Abciximab Monoclonal antibody cause platelet receptor blockade. Given IV max. effect seen with in 2hrs, DOA 10-12 hrs. Use- percutaneous angioplasty for coronary thrombosis Prevents restenosis, recurrent and death when used in conjugation with aspirin and heparin. Dose-0.25mg bolus---0.125microgm/kg/min for 12hrs IV AE-bleeding Contraindication same as fibrinolytics
  24. 24. Questions  Discuss in detail antiplatelet drugs. Add note on use of low dose Aspirin as an antiplatelet agent.  Short note:  Low dose Aspirin  Ticlopidine  Glycoprotein IIb/IIIa antagonists
  25. 25. Coagulation Phase Two major pathways • Intrinsic pathway • Extrinsic pathway 13 soluble factors are involved in clotting Biosynthesis of these factors are dependent on Vitamin K1 and K2 Most of these factors are proteases Normally inactive and sequentially activated Hereditary lack of clotting factors lead to hemophilia -A
  26. 26. Clotting factors 35
  27. 27. Intrinsic Pathway  All clotting factors are within the blood vessels  Clotting slower  Activated partial thromboplastin test (aPTT)  Blood sample + calcium  Mix with negatively charged phospholipid  Kaoline (aluminum silicate)  Determine clotting time  Generally clotting occurs in 26 to 33 seconds  Used to detect defects in the intrinsic pathway Extrinsic Pathway  Initiating factor outside the blood vessels - tissue factor  Clotting - faster - in Seconds  Prothrombin test (PT)  Tissue Thromboplastin factor III  Mix with phospholipid extract  Add calcium and blood sample  Determine clotting time  Generally 12 - 14 seconds  Used to detect defects in extrinsic pathway
  28. 28. Diagnosis of coagulation defects • Defective Intrinsic Pathway Prolonged APTT No change in PT • Defective Extrinsic Pathway No change in APTT Prolonged PT • Defective in Common pathway Prolonged APTT Prolonged PT
  29. 29. Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin II Thrombin IIa Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic Pathway Extrinsic Pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants
  30. 30. Activation Inactive XI Active XIa XIIa +
  31. 31. ANTICOAGULANTS  These are the drugs used to reduce coagulability of blood.  Classification In vitro anticoagulants In vivo anticoagulants Heparin A) -Heparin Sodium citrate -Low molecular weight Heparin Sodium oxalate -Danaparoid Sodium edetate -Lepirudin -Heparan sulfate B) Oral anticoagulants
  32. 32. B) Oral anticoagulants  Warfarin sodium  Bishydroxycoumarin (dicumarol)  Acenocoumarol  Phenindione
  33. 33. Heparin Chemistry & Occurence Straight chain mucopolysaccharide, glycosaminoglycans MW 10000-20000. Average=15,000 d (~45monosaccharide chains) Strongest organic acid in the body. Heparin is present in all tissues containing mast cells, richest source are liver, lung (bovine) and intestinal mucosa (porcine) LMWH isolated from standard heparin by gel filtration chromatography or partial depolymerization. (1000-10000 daltons).
  34. 34. MOA  Heparin binds to antithrombin III -----complex  Increases thrombin –AT reaction 1000folds.  Heparin induces conformational change in ATIII to expose its interactive sites.  Long heparin molecule provides scaffolding for clotting factors ( Xa & IIa) aswellas ATIII.  At low conc. interferes with intrinsic pathway while at high common pathway.  ATIII inhibits activated clotting factors of intrinsic and common pathway including thrombin, Xa, IXa and thus acts as Succide substrate
  35. 35. ATIII-SUCCIDE SUBSTRATE
  36. 36. Thrombin inhibition catalysed by heparin AT R H AT H AT H AT H R P P P P R R
  37. 37. FXa inhibition catalysed by heparin AT R H AT H AT H AT H R P P P P R R
  38. 38. Anticoagulant Properties of Heparin 1. Inhibits the thrombin-mediated conversion of fibrinogen to fibrin 2. Inhibits the aggregation of platelets by thrombin 3. Inhibits activation of fibrin stabilizing enzyme 4. Inhibits activated factors XII, XI, IX, X and II
  39. 39. Pharmacokinetics  Not effective orally  Sc/ iv administration  Onset immediate, peak in 5-10mins  Metabolized in liver  Excretion through kidney.
  40. 40. Unfractionated Heparin  High Dose  Treatment of venous/arterial thrombi  Requires monitoring  IV- 5,000 Units bolus, then 30,000-35,000 units/24 hrs  80 Units/kg bolus, then 18 Units/kg/hr to maintain aPTT in therapeutic range  therapeutic goal – 2-2.5 times normal control value (-30 sec)
  41. 41. Low Dose Unfractionated Heparin  Surgical Prophylaxis  5,000 Units SC 2 hr preop  5,000 Units SC every 12 hours  Medical Prophylaxis  5,000 Units SC every 12 hours  No monitoring required
  42. 42. ADVANTAGES OF LMWH 1. Less anti IIa activity than anti Xa activity 2. Good pk profile 3. More predictable dose response 4. Can be given by subcutaneous route 5. No monitoring required, can be given OPD basis 6. Less anti-platelet effects 7. Longer t1/2’s 8. Decreased hospital stay 9. More favorable benefit – risk ratio
  43. 43. LMWH  1mg/ kg S.C BD for DVT  30mg/ Kg S.C. for DVT prophylaxis of Knee and hip surgery  1mg/ kg S.C BD for DVT  30mg/ Kg S.C. for DVT prophylaxis of Knee and hip surgery
  44. 44. Adverse effects  Allergic and anaphylactic manifestations  Bleeding (1-33%)-antidote- Protamine sulphate  Heparin induced thromocytopenia. (more than 25%)  Alopecia  Osteoporosis  Hyperkalemia
  45. 45. Mechanisms of HIT  Type 1 (Non immune):  Fall in platelet count occurs within the first two days after heparin initiation, and returns to normal with continued heparin administration, and is of no clinical consequence.  Direct effect of heparin on platelet activation.  Type 2 (Immune):  Approx 0.3 to 3 percent of patients receiving heparin  Mediated by antibodies to a heparin-platelet factor 4 complex.  Seen with unfractionated heparin but in not with LMWH
  46. 46. Warfarin Warfarin, a coumarin derivative, is the most commonly used oral anticoagulant (OAC) . Warfarin is a vitamin K antagonist - Impairs the generation of active vitamin K, decreasing the amounts of vitamin K dependent coagulation factors • (FII, FVII, FIX, FX) Depending on factors such as age, risk factors, recurrence, etc., warfarin may be continued for anywhere from 1 month to lifelong
  47. 47. Oral anticoagulants : warfarin, dicumarol  Coumarins - warfarin, dicumarol  Isolated from clover leaves  Structurally related to vitamin K  Inhibits production of active clotting factors  Absorption rapid –high plasma protein binding binds to albumin  Clearance is slow - 36 hrs  Delayed onset 8 - 12 hrs  Overdose - reversed by vitamin K infusion  Can cross placenta - do not use during late pregnancies
  48. 48. Mechanism of action Descarboxy Prothrombin Prothrombin Reduced Vitamin K Oxidized Vitamin K NADHNAD Warfarin
  49. 49. Warfarin Monitoring • Why monitor? Need to balance proper anticoagulation without bleeding risk. • Monitored with PT, expressed as INR: Warfarin Monitoring • Where ISI = International Sensitivity Index, assigned by each thromboplastin manufacturer • Warfarin is given orally and titrated to achieve an INR of typically 2.0 – 3.0 INR = [Patient PT / Mean Normal PT]ISI
  50. 50. INR : International Normalized Ratio.  Different thromboplastins vary in sensitivity  To give PT values a consistent basis of comparison from lab to lab, WHO instituted the INR:  A uniform value in which the PT is expressed as a ratio.  Many manufacturers aim for an ISI of 1.0.  INR is affected by diet (because of the vitamin K dependent mechanism of action), other medications,  Monitored routinely, every 2 to 4 weeks
  51. 51. Drug interaction- Prototype Warfarin Category Mechanisms Examples of drugs Drugs that Increase Warfarin Activity Decrease binding to Albumin Aspirin, Sulfonamides Inhibit Degradation Cimetidine, Decrease synthesis of Clotting Factors Antibiotics (oral) Drugs that promote bleeding Inhibition of platelets Aspirin Inhibition of clotting Factors Heparin Antimetabolites Drugs decrease Warfarin activity Induction of metabolizing Enzymes Barbiturates Increases synthesis of Clotting Factors Vitamin K
  52. 52. New Anticoagulants Limitations of traditional anticoagulants, both with Heparin and Warfarin, have prompted the development of new agents
  53. 53. New Anticoagulants Parenteral FXa Inhibitors
  54. 54. FXa Inhibitors Parenteral synthetic pentasaccharide analogs • Synthetic and highly selective inhibitor of FXa • Acts as cofactor to AT • Administered by subcutaneous injection ONCE A DAY • Absolute bioavailability of 100% Fondaparinux (Arixtra®)
  55. 55. FXa Inhibitors Parenteral synthetic pentasaccharide analogs • LMW mixture of heparinoids (glycosaminoglycans, GAGs); acts as cofactor to AT • Anticoagulation effect is predominantly mediated by inhibition of FXa • Also has some anti-IIa effects • Fast acting, generally predictable dose response Danaparoid
  56. 56. Direct Thrombin Inhibitors • Recombinant hirudin, a derivative of the saliva of the medicinal leech Hirudo medicinalis • First direct thrombin inhibitor (DTI) to be approved by the FDA for anticoagulation in patients with (HIT) • Can be monitored with APTT, TT, chromogenic anti-IIa.
  57. 57. Direct Thrombin Inhibitors • A synthetic anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT) • Active against both free and clot- bound thrombin • Argatroban is typically monitored by APTT, but other methods like the chromogenic anti-IIa assay may be more accurate. Argatroban
  58. 58. Direct Thrombin Inhibitors • Synthetic polypeptide hirudin analog that interacts with the thrombin active site to reversibly inhibit thrombin • Alternative to heparin • Administered parenterally • Short half life • Monitored by Activated Clotting Time (ACT) Bivalirudin
  59. 59. Direct Thrombin Inhibitors • Studies have shown similar efficacy and bleeding risk to warfarin • Does not need monitoring • Was not FDA approved: more studies needed to assess liver failure risk Ximelagatran oral anticoagulant
  60. 60. The Extent of Thrombotic Disease Annually in the U.S. 1.5 million MIs-Mortality of 30% (450,000) 500,000 CVAs -Mortality of 30% (150,000) 2 million DVTs 200,000 deaths from PE
  61. 61. Venous Thromboembolism Third most common cardiovascular disease Significant morbidity and mortality VTE includes: • Deep Venous Thrombosis (DVT) • Pulmonary Embolism (PE)
  62. 62. Economy Class Syndrome Medical condition called Venous Thromboembolism Fibrin thrombi. 3months anticoagulants theraphy is required in DVT and PE For prophylaxis of pts.undergoing surgery--- LMWH—Decreases risk of leg vein thrombosis & PE. Anticoagulants are indicated for prophylaxis in bedridden, old, postoperative, post stroke, postpartum, leg fracture patients
  63. 63. Deep Vein Thrombosis  Blood clot of lower leg or thigh  Approximately 1 per 1,000 people affected by DVT  Hospitalization for 5 to 7 days  50% of patients with DVT are asymptomatic
  64. 64. Pulmonary Embolism Dislodged blood clot entering the pulmonary circulation Accounts for 5-10% of all hospital deaths 80% of patients die within the first 2 hours CT Scan of Pulmonary Embolism
  65. 65. Deep Vein ThrombosisEmbolusPulmonary Embolism
  66. 66. AMI AND UNSTABLE ANGINA Arterial thrombi-platelet thrombi Use of anticoagulants??? Beneficial in preventing mural thrombi at infarction site and venous thrombi in leg veins. Can be given for short periods till the Pt. is ambulatory. Heparin iv for 2-8 days followed by oral anticoagulant for 3 months. Short term use in unstable angina.
  67. 67. RHD, AF Warfarin / low dose aspirin / LMWH are effective in preventing stroke due to embolism from fibrillating atria. Warfarin the most effective. (3-4week theraphy)
  68. 68. Blood Hypercoagulability Increased procoagulants Decrease in inhibitors Impaired fibrinolysis Occurs in obstretic conditions, mallignancies, infections.
  69. 69. • Enhance degradation of clots • Activation of endogenous protease • Plasminogen (inactive form) is converted to Plasmin (active form) • Plasmin breaks down fibrin clots Fibrinolysis
  70. 70. FIBRINOLYTICS
  71. 71. • Streptokinase - bacterial product - continuous use - immune reaction • Urokinase - human tissue derived - no immune response • Tissue plasminogen activator (tPA) - genetically cloned - no immune reaction - EXPENSIVE FIBRINOLYTICS Inhibitors of fibrinolysis
  72. 72.  Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the pro-activator plasminogen.  This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin
  73. 73.  Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin.  Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse the thrombus from within
  74. 74.  Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs).  Activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation.  Human t-PA is manufactured as ALTEPLASE by means of recombinant DNA technology.
  75. 75.  RETEPLASE is less expensive than Alteplase. It lacks the major fibrin-binding domain thus is less fibrin-specific than Alteplase  TENECTEPLASE is a mutant form of t-PA that has a longer half-life, and it can be given as an intravenous bolus. Tenecteplase is slightly more fibrin-specific than Alteplase
  76. 76. DOSES • Dose:250000 U loading dose followed by 100000 U every hr for 24 -72 hrs Streptokinase • Loading dose of 300000 U followed by 300000 U/hr for 12 hrs Urokinase • 60mg iv over 1 hr followed by 40mg iv at a rate of 20mg/ hr Alteplase (t-PA)
  77. 77. Contraindications to Antithrombotic Therapy • Pre-existing coagulation or platelet defect, thrombocytopenia, or other bleeding abnormality • Inaccessible ulcerative lesion(e.g., gastrointestinal tract lesion) • Central nervous system lesion (e.g., caused by stroke, surgery, trauma) • Malignant hypertension • Advanced retinopathy • Old age (relative) • Aspirin or other antiplatelet drugs • Neoplastic disease General risk factors
  78. 78. Contraindications to Antithrombotic Therapy • Recent thoracic, abdominal, or central nervous system surgery • Recent cerebrovascular accident, trauma, or neoplasm • Bleeding ulcer • Anticipated invasive procedures (arterial punctures, biopsies, central lines) • Concurrent hemostatic dysfunction Specific to thrombolytic agents
  79. 79. • AMI • Multiple pulmonary emboli. • Pulmonary embolism with hemodynamic instability • Central DVT • Pheripheral vascular disease Indications
  80. 80. Drug preparations : to stop bleeding
  81. 81. Fibrinolytic Inhibitors: Aminocaproic Acid  Similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis  Competitively inhibits plasminogen activation  Oral dosage of EACA is 6 g four times a day  Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose followed by 30 mg/kg every 6 hours
  82. 82. USES  Adjunctive therapy in hemophilia  Bleeding from fibrinolytic therapy  Prophylaxis for re-bleeding from intracranial aneurysms.  Postsurgical gastrointestinal bleeding ,post prostatectomy bleeding ,bladder hemorrhage secondary to radiation and drug-induced cystitis.  Adverse effects  Intravascular thrombosis from inhibition of plasminogen activator  Hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness
  83. 83. Drug preparations: clotting deficiencies Vitamin K • Oral : 5 mg tablets Plasma fractions - for hemophilia • Antihemophilic factor ( VIII, AHF) • Parenteral Factor IX complex • Parenteral : in vials

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