4. Vascular Injury
Exposure of collagen and vWF Tissue factor exposure
Platelet adhesion and release Activation of coagulation
Platelet recruitment and
activation
Thrombin generation
Fibrin formationPlatelet aggregation
Platelet – fibrin thrombus
5. ANTI COAGULANTS
1] In vitro use
To prevent clotting of blood for transfusion or
diagnostic use
2] In vivo use
To prevent development & enlargement of thrombi
7. OXALATES
1} sodium oxalate – combines with blood calcium forming
insoluble calcium oxalate rendering calcium unavailable for
blood coagulation
Dose – conc of 20 % @ level of blood
0.01 ml / 1 ml blood ( 2mg/ml)
ALL OXALATE SALTS ARE TOXIC
Contraindicated – blood transfusion
-- systemic use
8. SODIUM FLUORIDE
• Excellent anticoagulant for blood glucose studies bcoz it
interferes with enzymes involved in glycolysis
• It acts as preservative
• Dose 2.5 mg / ml of blood for blood glucose preservation
9. ETHYLENE DIAMINE TETRA ACETIC ACID
• EDTA ( edetate disodium , USP )
MOA – Na & K salts of EDTA chelates blood calcium thus preventing
clotting
• Lab application
1} hematological count { thrombocyte count }
bcoz Cellular details preserved
Dose – 1 mg / 5 ml of blood
0.01 ml of 2 % EDTA solution / ml of blood
10. BLOOD TRANSFUSION
1] Acid Citrate Dextrose , USP
Sodium citrate – 25 g
Citric acid – 8 g
Dextrose – 24.5 g
Distilled water to make volume of 1000 ml
Dose – at level of 15 ml / 100 ml of blood
Toxicity in dogs should not cross 286mg/kg
11. `
2] Citric Phosphate Dextrose Adenine CPDA-1
In DOGS maintains high levels of erythrocyte post transfusion
viability up to 20 days
3] Heparin
In cats - To collect small quantity of blood ( 50 ml )for
transfusion
Lab purpose : 8 – 10 units of heparin / ml of blood
Blood transfusion : 4 – 6 units of heparin / ml of blood
12. SYSTEMIC ANTICOAGULANTS
1} Heparin & related compounds
2} Inhibitors of vitamin K
3} Direct inhibitors of coagulation factors
4} Miscellaneous anticoagulants
13. HEPARIN ( HEPARIN SODIUM , USP )
• Pharmaceutical graded heparin is prepared from bovine lung tissue
or porcine intestinal mucosa
• It is a heterogenous mixture of anionic sulfated mucopolysaccharide
with molecular weight ranging from 1200 – 40000 daltons.
• Sodium salts used in vivo.
• Calcium salts , potassium salts – therapeutic use.
14. MOA
• Anti coagulatory effect of heparin – the reversible binding of
heparin to AT III , a protease inhibitor & Heparin Co factor II
• Binded heparin accelerates the velocity of interaction between
coagulant inhibitory factors & clotting factors
• LMWH – inactivates only factor Xa
• HMWH – inactivates thrombin & blocks conversion of fibrinogen
to fibrin , neutralizes activated factor IX
15.
16. P K & P D
• Administered dose of heparin bounds extensively: endothelial cells
macrophages
plasma
proteins
Stored pools ~> saturated ~> free heparins ~>plasma ~> excretion
kidney
Metabolism – liver
- Reticulo endothelial system
17. CLINICAL INDICATION
• Prevention / treatment of venous thrombosis ( red thrombus )
• Pulmonary embolism
• Management of DIC
• Arterial fibrillation with embolization
Eg: feline cardiomyopathy
• Other potential coagulable states
Eg: cushing`s disease
nephrotic syndrome
cardiomyopathy
18. GUIDE LINE FOR HEPARIN DOSAGE
1} High dose heparin therapy
Aims to increase APTT 1.5 – 2.5 times base line & ACT 1.2 – 1.4
times base line
Initial high loading dose is beneficial
Regular & frequent monitoring of clotting time s essential
Clinical indication – treatment of established THROMBOEMBOLI
Dogs : 150 – 250 U / kg TID
Cats : 250 – 375 U / kg TID
19. 2} LOW DOSE HEPARIN THERAPY
Dogs : treatment & management of Heart worm infestation
Initial dose 100 – 200 U / kg i/v followed by 50 U / kg every 3 hours
Maintenance dose 40 – 80 U / kg TID s/c
Cats : treatment of feline cardiomyopathy
200 U / kg s/c TID
Horses : management of DIC
high grade DIC : 80 – 100 U / kg i/v after 4-5 hr repetation
low grade DIC : 25 – 40 U / kg s/c BID / TID daily
20. MANAGEMENT OF DIC ~ DISSEMINATED
INTRAVASCULAR COAGULOPATHY
Heparin + blood / plasma
Low dose regimen for management
Small animals : 75 U / kg TID
Horses : 25 – 100 U / kg TID
Effect on APTT = minimum
21. LOW MOLECULAR WEIGHT HEPARINS
• Are short chain of polysaccharide with molecular weight of 1000-
10000 Da
• Isolated from standard heparin by techniques
- Gel filtration chromatography
- differential precipitations with ethanol
Advantages: better absorption from s/c injection
: prolonged elimination half life
: lower incidences of hemorrhagic complications
22. MOA
• LMWH selectively inhibit factor Xa with little effect on thrombin ,
Factor II ~> result is little effect on APTT & whole blood clotting
time
• LMWH less anti platelet action
• Commercial preparations – Ardeparin , Bemiparin , Dalteparin ,
Enoxaparin , Reviparin ,
Nadroparin ,
Tinzaparin
23.
24. HEPARINOIDS
• Non heparin naturally occurring & synthetic sulphated
glycosaminoglycans which posses heparin like anticoagulant
action
1} DANAPAROID (Orgaron*)
Mixture of non heparin glycosamines isolated from porcine
intestinal mucosa
Orgaron* consists ~ heparin sulphate 80 %
~ dermatan sulphate 8 -16 %
~ chondroitin sulphate < 8.5 %
25. MOA
• Acts mainly by enhancing the inhibition of factor Xa by
antithrombine
• Danaproid exerts a strong catalytic effects on the inactivation of
factor Xa than on the inactivation of thrombin
Clinical indications
• Prevention of DEEP VEIN THROMBOSIS ( DVT ) following
orthopaedic , major abdominal & thoracic surgery
• Patients with positive diagnosis of non hemorrhagic stroke
27. VITAMIN K ANTAGONISTS
• Inhibitors of vitamin K often called as ORAL
ANTICOAGULANTS
• VIT K antagonists are active ORALLY (only IN VIVO )
• Studies in veterinary medicine focused primarily on their TOXIC
effects rather than on therapeutic indications
TYPES
1} Coumarin derivatives
2} Indanedione derivatives
28. COUMARIN DERIVATIVES
• Coumadins are synthetic oral anticoagulants derived from the
molecule 4 hydroxycoumarin
1} BISHYDROXYCOUMARIN – first oral AC synthesized by LINK
(1943-44)
Its a derivative of moldy / spoiled sweet clover which is responsible
for hemorrhagic disease in cattle in USA
2} WARFARIN SODIUM (USP)
2nd compound synthesized commercially
29. WARFARIN: MOA
• Inhibiton of hepatic synthesis of vit K dependent clotting
factor ~ Prothrombin
~ Factor VII , IX , X
~ anticoagulant protein C & S
Carboxylation results in the oxidative inactivation of vit K
Warfarin inhibits vit K epoxide reductase enzyme & interfere
with regeneration of active form of vit K thereby inhibiting
synthesis of prothrombin & factor VII , IX , X
30.
31. `
• Warfarin acts as AC only IN VIVO bcoz they act indirectly by
interfering with synthesis of clotting factors
• AC effects develops over several hours but peak plasma level
occurs in 1 hour after oral administration onset takes 6 -12 hours
with full benefits realized after (2-3 days) & long duration of
action (4-7 days)
• bcoz of persistence of factors synthesized before drug
administration & of long half life
• Rapidly & completely absorbed from intestine
• Metabolised in liver ~ inactive metabolites cytochrome P450
system
32. ADVERSE EFFECTS
• Acute internal bleeding/hemorrhage
• Clinical signs ~ anaemia , thrombocytopenia , hematuria etc
• Hemorrhages in brain & spinal column ~ ataxia , paresis ,
convulsions
• Periarticular hemorrhages ~ lamness , joint swelling , pain
LAB CONTROL
1} the quick test
2} the one stage prothrombin time
33. CLINICAL INDICATIONS
• Prophylaxis of venous thrombosis & Aortic/ pulmonary
thromboembolism
Horses : to relieve the clinical signs of NAVICULAR DISEASE
Dose @ 0.02 mg/kg PO once daily
Dogs : for prevention of recurrence of thrombotic conditions
Dose @ 0.1 – 0.2 mg/kg PO once daily
34. INDANEDIONE DERIVATIVES
• Are derivative of indane-1,3-dione
• Structurally related to coumarins & produce anticoagulation
activity by mechanism involving ANTAGONISM OF VITAMIN
K
• Reports to cause kidney damage, sensitivity reactions,
leucopenia in humans. Hence retricted drugs category
• Use in vety practice not reported yet
Eg: Anisindione , phenindione , clorindione , diphenadione
35. DIRECT INHIBITORS OF COAGULATION
FACTORS
1} Direct inhibitors of factor Xa – Xabans
-- Rivaroxabans
2} Direct inhibitors of coagulation factor II – hirudin
-- bivalirudin
-- desirudin &
lepirdin
3} Direct thrombin inhibitors – argatroban
-- dabigatran
37. THROMBOLYTICS
• Drugs that enhances the conversion of the inactive
precursor plasminogen to the active fibrinolytic enzyme
plasmin
• 2 phases Plasminogen ~ plasma/soluble phase
• ~ gel phase
• Dissolves both physiologic as well as pathogenic thrombus =
TOXIC ,producing hemorrhage = major side effect
38. MOA
• When plasminogen activating agents + clot = activation of fibrin
bound gel phase plasminogen to plasmin locally with selective
fibrinolysis
• Instead soluble phase plasminogen circulating in systemic blood
also activated
• Adverse effect = increased tendency for systemic bleeding
• Plasmin formation occurs through out circulation =
overactivation of plasminogen , neutralizing endogenous
antagonist to plasmin a2 ANTIPLASMIN
43. FIRST GEN : STREPTOKINASE
• Streptokinase is a protein obtained from group C BETA
HEMOLYTIC STREPTOCOCCI
• Effective & inexpensive clot dissolving drug ~ MI
• ~ Pulmonary
embolism
• MOA :acts as plasminogen activator = enhances production of
plasmin by forming an active non covalent 1:1 complex
(streptokinase : plasminogen complex )
• Plasmin catalyzes degradation of plasma proteins = clotting factor
FIBRINOGEN & factor V , VII
44. ADVERSE EFFECT
• Foreign protein = Antigenic reactions
• 2nd time use = hypersensitivity & Anaphylaxis
• Over dosage = plasminogen depletion & SK resistance
• Treatment over-dosage FRESH PLASMA /AMINOCAPROIC
ACID
45. CLINICAL INDICATIONS
• Used locally as powder , infusion or irrigation of wounds which
don’t responds for antibacterial therapy – burns , ulcers , chronic
eczema , ear hematomas , otitis externa , osteomyelitis , chronic
sinusitis
• Parentrally ~ eczema , dermatitis , hematoma , trauma &
pneumonia
• Prophylaxis ~ reduction of post operative adhesions
• Dogs: 5000 – 10,000 U (total dose) IM IV in 2 divided doses 5 days
• Large animals : 5000 – 10,000 U / 45 kg BW , IM IV 2 divided
dose 5 – 6 days
48. MOA
• It catalyzes conversion of plasminogen to plasmin
• Selective action towards the plasminogen bound to fibrin & low
affinity for free plasminogen
• Thus fibrinolysis to the formed clot , with out unwanted degradation
of other proteins
Clinical indication
1} thromboembolic strokes
2} deep vein thrombosis
3} pulmonary embolism to clear a blocked artery
49.
50. • ALTEPLASE – treatment of aortic thromboembolism
Cats : 0.25 – 1 mg/kg/hour , i/v infusion for total dose of 1-10
mg/kg
Dogs : 0.01 microgram/kg/min , i/v infusion for 30 min
• UROKINASE – to prevent post operative lesions
Dogs : 5000 – 10,000 units/kg , intra-peritoneal lavage
60. ANTITHROMBOTIC DRUGS
Antiplatelet drugs
Acetylsalicylic
acid (aspirin)
P2Y12
antagonists
Dipyridamole GPIIb/IIIa
antagonists
Used widely
in patients
at risk of
thromboembolic
disease
Beneficial in the
treatment and
prevention of ACS
and the prevention
of thromboembolic
events
Secondary
prevention in
patients following
stroke, often in
combination with
aspirin
Administered
intravenously, are
effective during
percutaneous
coronary
intervention (PCI)
61. COX INHIBITORS
• Aspirin ~ NSAID
• MOA = irreversibly inactivates cyclooxygenase enzyme to produce
pharmacological effects
Reduces synthesis of thromboxane A2 = potent vasoconstrictor &
inducer of platelet aggregation
• Irreversibly acetylate thromboxane synthase , enzyme responsible
for thromboxane synthesis
• Low dose = effective in reducing platelet aggregation
• High dose = blocks synthesis of prostacyclin reducing over all anti
aggregatory effect
62. Plaque Disruption
Collagen vWF
Platelet adhesion and secretion
Aspirin
Thrombin generation
Abciximab
Eptifibatide
Tirofiban
Platelet aggregation
Platelet recruitment and activation
X COX-1
TXA2
ADP
X
GPllb / llla activation
X
68. GLYCOPROTEIN II B / III A INHIBITORS
• NEW CLASES of potent platelet aggregation agonists
• MOA – acts by blocking glycoprotein II b / III a receptors present on
surface of platelets
• Glycoprotein II b / III a complex functions as receptor = vWB factor
through which agonists collagen , thrombin , thromboxanes , ADP
induces platelet aggregation
• Drugs:
1} Abciximax – treatment of ANGIOPLASTY
2} EPTIFIBTIDE
2} tirofiban
74. THROMBOXANE INHIBITORS
• Acts through inhibition of thromboxane synthetase = decreases
synthesis of TXA2 thus prevents platelet aggregation
• Elevates endogenous cAMP in the platelets by inhibiting
phosphodiesterase enzyme
• Blockade of cellular reuptake of adenosine into platelets ,RBC &
endothelial cells =increased extra cellular concentration of
adenosine
75. ,
1} DIPYRIDAMOLE
As synergistic with ASPIRIN
With WARFARIN – to decrease the incidence of thromboembolisim in
patients with PROSTHETIC HEART VALVES
2}DAZOXIBEN
3}PICOTAMIDE
4}TERUTROBAN
76. MISCELLANEOUS DRUGS
• CILOSTAZOL : phosphodiesterase inhibitor = intracellular
concentration of cAMP = increase in PK-A = inhibition of platelet
aggregation & arterial vasodilator effect
Treatment – muscular pains due to cramps , numbness or fatigue
• TIMOLOL ( b adrenoceptor blocker )
synergizes action of low dose aspirin
• SULFINPYRAZONE uricosuric drug related to phenylbutazone
Inhibits COX enzyme = blocks production of prostanoids
77. REFERENCES
• H RICHARD ADAMS Veterinary pharmacology and therapeutics, 8th edition.
• GOODMAN & GILMAN`S The pharmacological basis of therapeutics, 11th edition.
• HS SANDHU Essentials of veterinary pharmacology and toxicology, 2nd edition.
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