A Power point presentation on the fundamentals of "Anticoagulant Drugs" suitable for UG level Medical students

1. ANTICOAGULANTS
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong

2. Intrinsic Pathway
Extrinsic Pathway
Tissue Injury
Blood Vessel Injury
Recall !
XIIa
XII
Thromboplastin
XIa
XI
IXa
IX
VIIa
Xa
X
Factors affected
By Heparin
Prothrombin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Tissue Factor
Fibrinogen
XIII
VII
X
Thrombin
Fribrin monomer
Fibrin polymer

3. Why anticoagulants ?
To reduce the coagulability of blood
Blood clots – Thrombus
 Arterial Thrombosis:
 Adherence of platelets to arterial walls – “White” in color - Often
associated with MI, stroke and ischemia
 Venous Thrombosis:
 Develops in areas of stagnated blood flow (deep vein thrombosis),
“Red” in color- Associated with Congestive Heart Failure, Cancer,
Surgery
Thrombus dislodge from arteries and veins and become an embolus
Venous emboli can block arterioles in the lung and pulmonary
circulation
 Thromboembolism

4. Available Anticoagulants
Used in vivo:
1. Parenteral anticoagulants:
–
1.
–
Indirect thrombin inhibitors: Heparin, Low molecular weight heparin,
Fondaparinux, Danaparoid
Direct thrombin inhibitors: Lepirudin, Bivalirudin
Oral anticoagulants:
–
–
–
Coumarin Derivative: Bishydroxycoumarin (dicumarol), Warfarin sodium,
Acenocoumarol
Inandione derivatives: Phenindione
Direct factor Xa inhibitors: Rivaroxaban
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)

5. Heparin as Prototype
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
Types - (i) Regular or unfractionated (UFH) Heparin
(MW 5000 to 30,000) – IV or SC and (ii) LMWH (MW
2000 to 6000) – mostly SC

6. Heparin Actions
• 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
• 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

7. Heparin Actions – contd.
• 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
• 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

8. Heparin mechanism of action
Heparin
Antithrombin III
Thrombin

9. Heparin – Contd.
• 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
• Contraindications: Bleeding disorders, Severe
hypertension, GIT ulcer, Piles, SABE &
malignancy, Ocular & neurosurgery, Chronic
alcoholism, cirrhosis etc.
• Aspirin and antiplatelet drugs - caution

10. Low Molecular
Weight Heparin
(LMWH)
Interfered
PT
•
•
– 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)
aPTT
IP
N
P
EP
P
N
CP
P
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
P
•
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

11. Dosage of Heparin
• 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
• 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

12. Oral Anticoagulants

13. Warfarin
•
•
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

14. Warfarin – contd.
• 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
– 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)

15. Warfarin
• 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.
• Contraindications: Same as heparin
– Foetal warfarin syndrome: skeletal abnormality –
hypoplasia of nose, eye socket, hand bones and
growth retardation

16. Warfarin
• 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
• 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

17. FIBRINOLYTICS

18. Fibrinolytics
•
•
•
•
Drugs used to lyse thrombi/clot to
recanalize occluded vessels –
coronary artery
MOA: Produce more plasmin dissolves fibrin thread
Drugs: Streptokinase, urokinase,
alteplase (rt-PA), reteplase and
tenecteplase
Streptokinase – once popular
– Binds to plasminogen and generate
plasmin
– Non-specific – activates circulating +
fibrin bound plasminogen– nonspecific fibrinogen depletory – but
less effect than newer ones in
fibrinolysis

19. Alteplase and Tenecteplase
•
•
•
•
•
Recombinant tissue plasminogen activator (rt-PA) – human tissue culture
– costlier than Streptokinase
MOA: tissue specific thrombolytic (acts on fibrin bound plasminogen
within thrombus) – also interferes with circulating plasminogen (50%) –
inactivated by PAI-1
Plasma half life 5 minutes – given slow IV (heparin needed)
MI: 1o mg IV bolus – followed by rest 90 mg infusion for 90 minutes
Pulmonary embolism: 100 mg slow IV for 2 Hrs
genetically engineered, higher
fibrin selectivity, not inactivated by PAI-1, can
be injected over 10 seconds single bolus
• Tenecteplase:

20. Uses of Thrombolytics
• AMI – alternative to PCI with stent placement
– aspirin + heparin co-administered to prevent
re-occlusion
• DVT: leg, pelvis and shoulder
• Pulmonary embolism
• Stroke: selected patients

21. Antifibrinolytics
• Epsilon amino-caproic acid (EACA) and
Tranexamic acid
• MOA: Inhibit Plasminogen activation and clot
dissolution
• EACA: Specific antidote for fibrinolytic agents –
also adjunctive value in other conditions
• Tranexamic acid: More potent than EACA
– Uses: fibrinolytic drugs, Bypass surgery, Menorrhagia,
Recurrent epistaxis, tonsillectomy & tooth extraction
(haemophiliacs)

22. Antiplatelet Drugs (antithrombotic
drugs)

23. Antiplatelet Drugs (antithrombotic
drugs)
• Drugs which interferes with platelet function and used in
prophylaxis of thromboembolic disorders.
• Drugs: Aspirin, Dipyridamole, Ticlodipine, Clopidogrel and
Prasugrel
• Aspirin as antiplatelet:
– Irreversible Inhibition of COX 1 and TX synthase
– Suppress TXA2 (generated by platelets) in low doses (75-150 mg) – till
fresh platelets are formed – prolonged bleeding time
– Suppress COX-1 and decrease PGI2 synthesis in vessel wall – but
endothelial cells immediately re-synthesize fresh enzyme
– Also inhibits release of ADP from platelets and their sticking to each
other – but not to adhesion to damaged vessel walls

24. Antithrombotic drugs - Dipyridamole
• Powerful coronary dilator – increases total
coronary flow
• MOA: Adeosine is local mediator involved in
autoregulation of coronary flow in response to
Ischaemia
– Dipyridamole prevents uptake and degradation of
adenosine and increases platelete cAMP – potentiates
PGI2 – interferes platelete aggregation
• Uses: Enhance antiplatelet action of Aspirin –
lowers the risks of TIAs – 150-300 mg / day

25. Antithrombotic drugs - Ticlodipine
• First thienopyridine derivative – Prodrug (active
metabolites in liver)
• MOA: Inhibits fibrinogen as well as ADP induced platelet
aggregation
– Gi coupled P2Y12 (P2YAC) purinergic receptors mediate adeylyl
cyclase inhibition due to ADP – blocked irreversibly
– No effect on TXA2
– Irreversible blockade of P2YAC – platelet inhibiton cumulates –
effects appear in 8-10 days
• Uses: Stroke prevention, TIA, intermittent claudication,
unstable angina, coronary bypass, prevention of MI
• Serious ADRs – Bleeding, neutropenia, hamolysis,
thrombocytopenia and jaundice - replaced by Clopidogrel

26. Antithrombotic drugs - Clopidogrel
• Similar MOA to Ticlodipine – irreversible blockade of platelet
function
– Safer and better tolerated than Ticlodipine
• Advantages over Aspirin in Ischaemia – lower incidence of
ischaemic events
• Synergistic action with aspirin – prevention of Ischaemic episodes
• Kinetics: Prodrug like Ticlodipine, 50% absorbed orally
– Only a fraction slowly activated in liver by CYP2C19 slow acting
– CYP2C19 – genetic polymorphism - interindivdual variability in
antiplatelet action
– Takes 5-7 days for action
• ADRs: Bleeding most common, neutropenia and thrombocytopenia
rarely
• Dose: 75 mg OD

27. Antithrombotics – Other Drugs
• Prasugrel: Faster and potent P2Y12 (P2YAC)
purinergic receptors Blocker
• Newer Drugs: Glycoprotein (GP) IIb/IIIa receptor
antagonists: Abciximab, Ebtifibatide and Tirofiban
– Newer class of drugs
– Blocks the key receptor involved in platelet
aggregation
– Collagens, thrombin, TXA2 and ADP etc. – acts
through - GLP IIb/IIIa is an adhesive receptor
(integrin) on platelet surface
– GLP IIb/IIIa antagonists block platelet aggregation

28. Uses of antithrombotics
• Coronary Artery Disease: Aspirin 75-150 mg/day in all
individuals with evidence of coronary artery disease –
clopidogrel is an alternative in ischaemia
• Acute Coronary Syndromes: Aspirin 325 mg orally and
LMW heparin – NSTEMI and STEMI
• Cerebrovascular accidents: Do not alter the course of
cerebral thrombosis – reduces incidence of TIA
• Prosthetic Heart Valves and arteriovenous shunts: In
conjunction with warfarin
• Venous thrombosis: DVT and PE
• Peripheral vascular disease

29. Must Know
•
•
•
•
Heparin, LMWH and Protamine sulfate
Warfarin
Fibrinolytics (Thrombolytics)
Antiplatelet Drugs – Aspirin, Dipyrydamole
and Clopidogrel

30. THANK YOU