by Dr. Vishal Pawar, MD Pharmacology a comprehensive review of anticoagulants and their effects

1. ANTICOAGULANTS
BY: DR. VISHAL PAWAR
JR – 1
DEPT. OF PHARMACOLOGY

2. BLOOD COAGULATION

3. EXTRINSIC PATHWAY
• Occurs within 2 seconds - Tissue trauma
• Tissue factor (factor III) leaks into blood (extrinsic)
• In Vitro
STAGE 1

5.  Occurs over several minutes
 When in contact with glass or endothelial damage
 In Vivo
INTRINSIC PATHWAY

7. STAGE 2

8. Thrombin
Ca++
Fibrinogen Fibrin Insoluble
XIIIa Ca++
Stabilised Fibrin threads
STAGE 3

9.  PROSTACYCLIN (PGI 2)
 Produced – endothelial cells
 Opposes action of Thromboaxane A2
 Thus inhibits platelet aggregation and release
NATURAL ANTICOAGULANT MECHANISM

10.  ANTITHROMBIN III (AT III)
 Inhibits factors II, IX, X, XI, XII
 PROTEIN C
 Enhances Tissue Plasminogen Activator (t-PA)
 Endogenous
 Vitamin K dependent
 Activated by thrombin

11.  HEPARAN SULFATE
 Proteoglycan
 Endothelial cells
 Co factor
 Increases AT III activity

12.  PARENTERAL
 Indirect thrombin inhibitors:
Unfractionated Heparin (UFH)
Low Molecular Weight Heparin (LMWH)
Fondaparinux
 Direct thrombin inhibitors: Hirudin, Lepirudin
Bivalirudin, Desirudin
Argatroban, Danaparoid
Drotreocogin Alpha
ANTICOAGULANTS

13.  ORAL
 Coumarin derivative: Warfarin
Dicumarol
Acenocoumarol
Ethylbiscoumacetate
 Thrombin inhibitiors: Rivaroxiban
Dabigatran
 Indanedione derivative: Phenindione
Anisindione

14. PARENTERALANTICOAGULANTS

15.  Sulfated mucopolysaccharide mixture
 Molecular Weight: 10,000 – 40,000
 Present with histamine in all tissues containing mast cell
 Richest source: lung, liver, intestinal mucosa
HEPARIN

17.  PHARMACOKINETICS
 Not absorbed from Gastro Intestinal Tract (GIT)
 Doesn’t cross Blood Brain Barrier (BBB)
 Administered in Ca++, Na++ salts – I.V, S.C
 Never I.M
 Antagonist – Protamine Sulfate
 I.V, 1 mg for 100 units of heparin

18.  Monitoring: activated partial thromboplastin time (aPTT)
 Toxicity:
 Bleeding – decreased by proper patient selection, careful control
of dosage, close monitoring
 Hypersensitivity: animal origin
 Long term treatment: osteoporosis, spontaneous fractures

19.  Systemic hypercoaguable state
 Venous thrombus
 Measures:
• Platelet counts
• Thrombocytopenia appearing in time frame – suspicious HIT
• Any new thrombus – suspicious HIT
 Treatment: discontinue heparin, substitute – direct thrombin
inhibitor
HEPARIN INDUCED THROMBOCYTOPENIA (HIT)

20.  Inhibits Xa
 Advantages:
• S.C, better bioavailability
• Longer half life
• Doesn’t prolong clotting time – predicted response
• No monitoring
• Dose in ‘mg’
 Example: Enoxaparin, Dalteparin, Reviparin
LMWH

21.  PARENTERAL
 Hirudin:
• Obtained from salivary glands of leech
• Specific irreversible inhibitor
• I.V.
 Lepirudin: recombinant form
DIRECT THROMBIN INHIBITORS

22.  Bivalirudin: alternative to heparin in Percutaneous Coronary
Angioplasty
 Desirudin: Deep Vein Thrombosis (DVT)
 Argatroban: patients with heparin induced thrombocytopenia,
alternative to lepirudin

23.  Danaparoid
• 84% heparan sulfate + 12% dermatan sulfate + 4% chondroitin
sulfate
• Prevention of post operative DVT following hip surgery
 Drotreocrogin Alpha
• Human recombinant Protein C
• Inhibits factor Va, VIIIa
• Decrease mortality risk from severe sepsis

24. ORAL ANICOAGULANTS

25.  Prevention of DVT in Hip/knee surgery
 No monitoring
 Fixed doses
 Shorter half life than warfarin
 Equivalent to LMWH, in safety and efficacy
ORAL THROMBIN INHIBITORS

26.  DABIGATRAN ETEXILATE MESYLATE
 First approved by FDA in 2010
 Reduces risk – stroke and systemic embolism with non vascular
fibrillation
 Oral bioavailability: 3-7 %
 Half life: 12-17 hours

27.  Dosage: 150 mg BD
 No monitoring
 Toxicity: bleeding
 No antidote

28.  RIVAROXABAN
 Inhibits factor Xa
 Increased oral availability with food
 Peak plasma level: within 2-4 hours
 Substrate for P450 system and P Glycoprotein transporter
 Drugs which inhibit – increases its effect, example – ketoconazole
 Half life: 5-9 hours, aged 20-45 years
 Increases in elderly and renal/hepatic function impaired

29. Continued...
 Approved: prevention embolic stroke in atrial fibrillation (AF)
without valvular heart disease
 Prevention of venous thromboembolism following hip/knee
surgery
 Prophylactic dose: 10 mg  35 days – hip replacement
 12 days – knee surgery

30. COUMARIN DERIVATIVES

31.  Competitively inhibits Vitamin K (Vit. K) Reductase
 In turn inhibits synthesis factor II, VII, IX, X by liver
 Anticoagulant effect takes – 1-3 days
 Factor VII – depresses earlier
 Prothrombin (factor II) – diminished last
 Monitoring: Prothrombin time (PT)
 Antagonist: Vit. K, Fresh Frozen Plasma (FFP)
WARFARIN

33.  PHARMACOKINETICS
 Oral bioavailability  100%
 99% plasma bound
 Longer half life
 Several drug displacement reactions
 Metabolised by liver, Enterohepatic circulation
 Partly conjugated with glucoronic acid, excreted – kidney

34.  INCREASED ACTIVITY:
 Enzyme inhibitors (P450 CYP2C9) :
 Displace it : Cotrimoxazole
Indomethacin
Phenytoin
DRUG INTERACTIONS
Sulfinpyrazone
Metronidazole
Disulfiram
Erythromycin
Allopurinol
Amiodarone
Cimetidine
Chloramphenicol

35.  Platelet aggregation Inhibitors: Aspirin
 Gut flora inhibitors, reduce Vit. K synthesis: Broad spectrum
antibiotics
 Causing Hypoprothrombinemia: III generation cephalosporin,
ex. Cefoperazone
 Miscellaneous:
Hepatic disease  decreases factor synthesis
Hyperthyroidism  increases catabolism of factors

36.  DECREASED ACTIVITY
 Enzyme inducers: Barbiturate
Rifampicin
Griseofulvin
Carbamazapine
 Absorption inhibition: Cholesyatramine
Sucralfate
 Increases factor synthesis: OC Pill
 Miscellaneous: Hypothyroidism, Hereditary resistance

37.  Prevent thrombus extension, recurrence, embolic complication
by decreasing thrombin formation
 Initially, Heparin (rapid onset) + oral anticoagulants started
concurrently
 Heparin discontinued – 6-7 days
USES OF ANTICOAGULANTS

38.  Prevention, Treatment: DVT and Pulmonary Embolism
 Prophylaxis: Heparin  5000 units, S.C, BD
LMWH  30 mg, S.C, OD
advantage LMWH – no monitoring, minimum risk of bleeding
 Established Venous Thrombus:
• Heparin  I.V bolus 5000-10,000 units
• Followed by I.V infusion 1000 units per hour
• 6-7 days with last 3 days Warfarin overlap

39. Continued...
Warfarin  initially 10-15 mg oral per day
with prothrombin time
reduce plasma thrombin concentration to 25% of
normal value
Maintainance  5-7 mg per day
 Myocardial Infarction (MI): arterial thrombi (platelet),
less effective, prevent secondary thrombus

40.  Unstable angina: Decreases chance of MI
Aspirin + Heparin, followed warfarin
 Rheumatic Heart Disease: Warfarin/LMWH/Low dose Aspirin
 Miscellaneous:
• Disseminated Intravascular Coagulation
• Peripheral Embolism (example: Retinal vessel)
• Cardiac bypass and valve replacement
• Extracorporal circulation
• Pregnancy

41.  Most common: HAEMORRHAGE
 HEPARIN
 Thrombocytopenia
 Osteoporosis
 Transient Alopecia
 Hypersensitivity
ADVERSE EFFECTS OF ANTICOAGULANTS

42.  WARFARIN
• Teratogenic
• Transient alopecia
• Dermatitis
• Diarrhoea

43.  HEPARIN
 Bleeding Disorders
 Thrombocytopenia
 Severe Hypertension
 Subacute Bacterial Endocarditis (SABE)
 Tuberculosis
 Concurrent use of antiplatelet drugs
 WARFARIN
Same as Heparin + Pregnancy
CONTRAINDICATIONS

44.  Anticoagulants are a basic need for treatment of thromboembolic
events
 Heparin and warfarin form the mainstay of treatment, prevention
 Newer oral anticoagulants, consistently shown equivalent efficacy, in
addition offering lower bleeding rates, rapid therapeutic effect, no
need of monitoring
 Hence are replacing the dominance of warfarin and heparin in
prevention and treatment of thrombotic diseases
CONCLUSION

45.  Goodman and Gilman’s, Blood coagulation and anticoagulant, chapter
30, the pharmacological basis of therapeutics,12th edition, 849
 Bertram G. Katzung, Anthony J. Trevor, Drugs used in Disorders of
coagulation, Chapter 34, Basic and Clinical Pharmacology, 13th edition,
584
 Atrial fibrillation, oral anticoagulant drugs, and their reversal agents
[Internet]. Fda.gov. 2016 [cited 30 December 2016]. Available from:
http://www.fda.gov/drugs/newsevents/ucm467203.htm
REFERENCES

46.  J P. Dawn of the direct-acting oral anticoagulants: trends in oral
anticoagulant prescribing in Wales 2009-2015. - PubMed - NCBI
[Internet]. Ncbi.nlm.nih.gov. 2016 [cited 30 December 2016]. Available
from: https://www.ncbi.nlm.nih.gov/pubmed/28000318
 K D Tripathi, Drugs affecting coagulation, essentials of medical
pharmacology, 7th edition, chapter 44, 613
 H Sharma, drugs affecting coagulation, principles of pharmacology,
2nd edition, chapter 51, 654

47. THANK YOU