Anticoagulant drugs

1. ANTICOAGULANTS and ANTIPLATELET
Dr C M Kamaal MD, DCH
Associate Professor in Pharmacology
SMMH Govt. Medical College
Saharanpur Uttar Pradesh

2. ANTICOAGULANTS
Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the
bite area unclotted long enough for the animal to obtain some blood.

3. ANTICOAGULANTS
• Anticoagulants, commonly known as blood thinners, are chemical substances
that prevent or reduce coagulation of blood, prolonging the clotting time.
• As a class of medications, anticoagulants are used in therapy for thrombotic
disorders
• Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and
various intravenous anticoagulant dosage forms are used in hospitals.
• Some anticoagulants are used in medical equipment, such as sample tubes,
blood transfusion bags, heart-lung machines, and dialysis equipment.

4. Haemostasis

11. • A prothrombin time (PT) is a test used to help detect and diagnose a bleeding disorder or
excessive clotting disorder; the international normalized ratio (INR) is calculated from a PT result
and is used to monitor how well the blood-thinning medication (anticoagulant) warfarin is
working to prevent blood
• In healthy people an INR of 1.1 or below is considered normal. An INR range of 2.0 to 3.0 is
generally an effective therapeutic range for people taking warfarin for disorders such as atrial
fibrillation or a blood clot in the leg or lung
• INR stands for international normalized ratio and is measured with a blood test called PT-INR. PT
stands for prothrombin time. The test measures how much time it takes for your blood to clot
and will determine if one is receiving the right dose of warfarin.
• For patients who are on anticoagulant therapy, the therapeutic INR ranges between 2.0 to
3.0. INR levels above 4.9 are considered critical values and increase the risk of bleeding

12. Blood coagulation pathway

15. COAGULANTS
Fresh Frozen plasma
Fresh whole blood or fresh frozen plasma
provide all the factors needed for coagulation
and are the best therapy for deficiency of any
clotting factor. Moreover, they act immediately.
Non-pharmacological

16. COAGULANT MEDICATIONS
• Substances which promote coagulation,
• Indicated in haemorrhagic states.

17. COAGULANT MEDICATIONS
Vitamin K
 Phytonadione
 Menadione
 Acetomenaphthone
Miscellaneous
 Fibrinogen
 Antihaemophilic factor
 Desmopressin
 Adrenochrome monosemicarbazone
 Ethamsylate
 Rutin

18. VITAMIN K
• Koagulations vitamin (vit K)
• Vit K acts as a cofactor at a late stage in the synthesis by liver of coagulation proteins
prothrombin
• Fat-soluble forms of vit K are absorbed from the intestine via lymph and require bile salts
for absorption, while water soluble forms are absorbed directly into portal blood.in,
factors VII, IX and X.
• Deficiency of vit K occurs due to liver disease, obstructive jaundice, malabsorption and
long-term antimicrobial therapy which alters intestinal flora
• The most important manifestation is bleeding tendency due to lowering of the levels of
prothrombin and other clotting factors in blood.
• Haematuria is usually first to occur; other common sites of bleeding are g.i.t., nose and
under the skin—ecchymoses.

19. Koagulations vitamin (vit K)
Phytomenadione

21. Adrenochrome Monosemicarbazone (50IU) + Rutin (10IU) + Menadione Sodium Bisulfite (200IU) +
Vitamin D (125mg) + Calcium Phosphate (37.5mg)

23. Treatment of bleeding due to deficiency of clotting factors in the following situations:
Uses of Vitamin K

24. Antihaemophilic factor
• It is concentrated human AHG or antihaemophilic globulin (factor VIII)
prepared from pooled human plasma.
• It is indicated (along with human fibrinogen) in haemophilia A
which is due to AHG deficiency.

25. Adrenochrome monosemicarbazone
• It is believed to reduce capillary fragility, control oozing from raw
• surfaces and prevent microvessel bleeding, e.g. epistaxis, haematuria,
• secondary haemorrhage from wounds, etc.
STYPTOCHROME 3 mg/2 ml inj., STYPTOCID: 2 mg/2 ml inj.

26. Ethamsylate
• It reduces capillary bleeding when platelets are adequate; probably corrects abnormalities
of platelet adhesion, but does not stabilize fibrin (not an antifibrinolytic).
• Ethamsylate has been used in the prevention and treatment of capillary bleeding in
menorrhagia, after abortion, epistaxis, malena, hematuria and after tooth extraction
• Efficacy is not supported by significant evidences
ETHAMSYL 250, 500 mg tabs; 250 mg/2 ml inj.

27. LOCAL HAEMOSTATICS (STYPTICS)
• Substances used to stop bleeding from a local and approachable sites
• Particularly effective on oozing surfaces, e.g. tooth socket, abrasions, etc
• Absorbable materials like fibrin (prepared from human plasma and dryed as sheet or foam),
gelatin foam, oxidized cellulose.
• Vasoconstrictors like 0.1% Adrenaline solution may be soaked in sterile cotton-gauze and
packed in the bleeding tooth socket or nose in case of epistaxis to check bleeding

28. ANTICOAGULANTS
Drugs used to reduce the coagulability of blood.
PARENTERAL
Vitamin K antagonist
• Bishydroxycoumarin
(dicumarol)
• Warfarin sodium
• Acenocoumarol
(Nicoumalone)
• Ethylbiscoumacetate
Direct Factor Xa
inhibitor
• Rivaroxaban
• Apixaban
Oral direct thrombin
inhibitor
• Dabigatran etexilate
Indirect thrombin
inhibitor
• Heparin (UFD or
unfractioned)
• Low molecular weight
(LMW) heparins
Enoxaparin, Reviparin,
Nadroparin, Dalteparin,
Parnaparin, Ardeparin
• Fondaparinux
• Danaparoid
Direct thrombin
inhibitor
• Bivalirudin
• Argatroban
ORAL

30. Site of action anticoagulants

31. HEPARIN
• Heparin is a large, highly ionized molecule; therefore not absorbed orally.
• Straight chain mucopolysaccharides with Molecular weight 10,000 to 20,000.
• Powerful and instantaneously acting anticoagulant, effective both in vivo and in vitro.
• It acts indirectly by activating plasma antithrombin III
• The anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin (IIa) mediated
conversion of fibrinogen to fibrin.
• Low concentrations of heparin prolong aPTT without significantly prolonging PT. High concentrations prolong
both. Thus, low concentrations interfere selectively with the intrinsic pathway affecting amplification and
continuation of clotting, while high concentrations affect the common pathway as well.
• Low molecular weight heparin, which is insufficient to provide a long scaffolding, selectively inhibits factor Xa
• Heparin does not cross blood-brain barrier or placenta (it is the anticoagulant of choice during pregnancy)
• Heparin is not orally absorbed, presumably because of its size and polyanionic charge, and hence
is administered parenterally, either by continuous or intermittent infusion or by subcutaneous (SC) injection.

32. HEPARIN
Unfractioned(UFH)
Or
Heparin
LMWH
(Low molecular weight Heparin)
• Unfractionated heparin (UFH) as a pharmaceutical is heparin that has not been fractionated to sequester the
fraction of molecules with low molecular weight. In contrast, low-molecular-weight heparin (LMWH) has
undergone fractionation for the purpose of making its pharmacodynamics more predictable.
• Low Molecular Weight Heparin (LMWH), as its name suggests, is derived from Unfractionated Heparin (UFH) by
digestion or depolymerization of longer chains of heparin into shorter chains by chemical or enzymatic means.
These short strands make LMWH last longer and act more predictably in the body than UFH

33. Unfractioned(UFH)
Or
HEPARIN
LMWH
(Low molecular weight Heparin)

34. Enoxaparin
• Enoxaparin is available as an injectable medicine that helps prevent blood clots in the legs and other
parts of the body. If these blood clots are not prevented, they can travel to the lungs and cause serious
complications and even death.
• After a patient has surgery, such as hip or knee replacement or in some cases abdominal surgery,
enoxaparin is often used for several days to up to a month to prevent blood clots. This medicine is also
used to prevent blood clots in patients confined to bed and also for patients experiencing chest pain and
heart attacks.
• Enoxaparin belongs to a class of drugs known as “low molecular weight heparin” (LMWH), which is
different than heparin, another drug that helps to prevent blood clots.

35. Quick penetrating solution (QPS)
• A quick penetrating solution (QPS) formulation of heparin 1000 u/ml has been recently developed
for topical application to speed up healing of post-infusion superficial thrombophebitis.
PHLEBOTROY QPS 1000 u/ml topical solution; 5 ml bottle; apply on the lesion 3 times a day

37. • Heparin should not be mixed with penicillin,
tetracyclines, hydrocortisone or NA in the same
syringe or infusion bottle.
• Heparinized blood is not suitable for blood
counts (alters the shape of RBCs and WBCs),
fragility testing and complement fixation tests.

38. Advantages of LMWH
• Better subcutaneous bioavailability (70–90%)
compared to UFH (20–30%): No need continuous IV
infusion and monitoring.
• Variability in response is minimized.
• Longer and more consistent monoexponential t½ (4–
6 hours); making possible once daily s.c.
administration.
• Since aPTT/clotting times are not prolonged,
laboratory monitoring is not needed; dose is
calculated on body weight basis.
• Risk of osteoporosis after long term use is much less
with LMW heparin compared with UFH.

39. Indications of LMWH
• Prophylaxis of deep vein thrombosis (dVT)and pulmonary embolism (PE) in high-risk patients undergoing
surgery; stroke or other immobilized patients.
• Treatment of established DVT.
• Unstable angina (UA) and MI: they have largely replaced continuous infusion of UFH.
• To maintain patency of cannulae and shunts in dialysis patients.

40. ADVERSE EFFECTS OF HEPARIN
• Bleeding due to overdose is the most serious complication of heparin therapy. Since heparin
(and other anticoagulants) interfere with secondary haemostasis, bleeding from deeper
organs is more common. Haematuria is generally the first sign; other sites are g.i. tract,
brain, joints, muscles, etc.
• Heparin-induced thrombocytopenia (HIT) is another common problem. In some patients
antibodies are formed to the heparin-platelet complex and marked depletion of platelets
occurs—heparin should be discontinued in such cases. Even molecular weight (LMW)
heparins are not safe in such patients, and they should be treated with a direct thrombin
inhibitor.
Other adverse effects
• Transient and reversible alopecia
• Increased serum transaminase
• Osteoporosis on long-term use
• Hypersensitivity reactions

41. CONTRAINDICATIONS
• Bleeding disorders, history of HIT.
• Severe hypertension (risk of cerebral haemorrhage), threatened abortion,
piles, g.i. ulcers (risk of aggravated bleeding).
• Subacute bacterial endocarditis (risk of embolism), large malignancies (risk
of bleeding in the central necrosed area of the tumour), tuberculosis (risk
of haemoptysis).
• Ocular and neurosurgery, lumbar puncture.
• Chronic alcoholics, cirrhosis, renal failure.
• Aspirin and other antiplatelet drugs should be used very cautiously during
heparin therapy.

42. Fondaparinux
• It is longer acting (t½ 17 hours).
• A longer acting alternative to LMW heparins
• Metabolism is minimal, and it is largely excreted unchanged
by the kidney. As such, it is not to be used in renal failure
patients.
• Fondaparinux is less likely to cause thrombocytopenia
compared to even LMW heparins. Risk of bleeding is also less
and incidence of osteoporosis after prolonged use is minimal.
• Fondaparinux does not require laboratory monitoring of aPTT.
• It is indicated for prophylaxis and treatment of DVT and PE, as
well as in acute coronary syndromes (ACS) when immediate
intervention is not planned.

43. Protamine sulfate
• Given i.v. it neutralizes heparin
• Protamine is more commonly used when heparin action needs to be
terminated rapidly, e.g. after cardiac or vascular surgery.
• It only partially reverses the anticoagulant effect of LMW heparins.
Heparin Antagonists

44. DIRECT THROMBIN INHIBITORS (dTIs)
Bivalirudin
• Congener of the larger polypeptide anticoagulant hirudin secreted by the salivary glands of leech
• It is a specific and reversible DTI with quick onset and short lasting anticoagulant action, which is more
predictable and consistent than that of UFH
• There is no risk of HIT with bivalirudin, and this probably is its most significant feature.
• Bivalirudin is indicated as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) for
STEMI. It is to be used along with an antiplatelet drug viz. aspirin and/ or clopidogrel or a glycoprotein IIb/IIIa
inhibitor (GPI). It can also be used in unstable angina (UA) and NSTEMI when urgent or early PCI is planned.

45. ORAL ANTICOAGULANTS
• By convention, the term ‘Oral anticoagulant’ refers to the warfarin-like drugs which act by
blocking synthesis of clotting factors.
• However lately, several orally active direct factor Xa inhibitors and direct thrombin
inhibitors have also become available, and are increasingly used.

46. VITAMIN K Antagonists
Coumarin derivatives
Warfarin
• Oral anticoagulants are derived from coumarin, which is found in many plants. A prominent member
of this class is warfarin (Coumadin)
• Warfarin and its congeners act indirectly by interfering with the synthesis of Vit K dependent clotting
factors in liver.
• It takes at least 48 to 72 hours for the anticoagulant effect to develop. Where an immediate effect is
required, heparin must be given concomitantly.
• Racemic Warfarin sodium is the most popular coumarin anticoagulant. The commercial preparation
of warfarin is a mixture of R (dextrorotatory) and S (levorotatory) enantiomers.
• The dose of vit K antagonist oral anticoagulant must be individualised by repeated measurement of
prothrombin time and INR

47. Racemic Warfarin
Warfarin

48. • Warfarin induced bruise

49. Warfarin related bleeding
• Bleeding as a result of extension of the desired pharmacological action is the most important
problem causing bruise, ecchymosis, epistaxis, hematuria, bleeding in the g.i.t. Intracranial or other
internal haemorrhagesmay even be fatal.
• Bleeding is more likely if therapy is not properly monitored, or when the International normalized
ratio (INR) exceeds 4, or interacting drugs/contraindications are present
• Treatment:
• Withhold the anticoagulant.
• Give fresh blood transfusion; this supplies ready made clotting factors and replenishes lost blood.
Alternatively fresh frozen plasma may be used as a source of clotting factors.
• Give vit K1 which is the specific antidote but it takes 6–24 hours for the clotting factors to be
resynthesized and released in the blood after vit K administration

50. Warfarin embryopathy
Fetal warfarin syndrome
• Fetal warfarin syndrome is a disorder of the embryo which
occurs in a child whose mother took the medication warfarin
during pregnancy
• Resulting abnormalities include low birth weight, slower
growth, mental retardation, deafness, small head size, and
malformed bones, cartilage, and joints

51. Limitation with use of Warfarin
• Delayed onset of action
• Slow recovery on stoppage
• Narrow therapeutic range,
• Need for repeated laboratory monitoring
• Dose adjustment
• Numerous drug interactions.

53. Rivaroxaban
• Oral directly acting Xa inhibitor
• Anticoagulant action develops rapidly within 3–4 hours of ingestion and lasts for ~24 hours.
• It is largely metabolized, but also excreted unchanged in urine; plasma t½ is 7–11 hours.
• Another advantage is that it requires no laboratory monitoring of PT or aPTT
Uses
• Prophylaxis of venous thromboembolism following total knee/hip replacement
• Prophylaxis and treatment of DVT.
• Prophylaxis of acute coronary syndrome

54. Clinical points in use of anticoagulants
• Use requires great caution and expertise.
• They do not dissolve already formed clot, but prevent recurrences.
• Parenteral anticoagulants, viz. UFH, LMW heparins, fondaparinux are utilized for rapid and short-term action, while oral
anticoagulants warfarin, factor Xa inhibitors and oral DTIs are suitable for maintenance therapy
• Anticoagulants are most effective for prevention and treatment of VTE, because venous thrombi are mainly fibrin thrombi
• Oral f.XaIs and DTIs have surpassed low dose s.c. heparin and LMW heparins for prevention of VTE in post-knee/hip
replacement surgery patients.
• LMW heparins and fondaparinux have almost replaced UFH, except in kidney disease patients, because clearance of
UFH is affected to a lesser extent by renal failure.
• UFH is also preferred as prophylactic in major surgery and high risk cases, because its action can be rapidly reversed by
protamine, which neutralizes LMW heparins to a lesser extent, and does not neutralise fondaparinux.
• Anticoagulants are of limited and inconsistent benefit in arterial thrombosis, because arterial thrombi are mainly
composed of platelets. Their use in MI and UA is short term and secondary to that of antiplatelet drugs.
• Antiplatelet drugs are superior to anticoagulants in transient ischaemic attacks (TIAs)
• The parenteral DTI bivalirudin is specifically indicated in patients with HIT, or those who are at risk of developing HIT.

56. • These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels
(mainly coronary artery). They are therapeutic rather than prophylactic and work by
activating the natural fibrinolytic system
FIBRINOLYTIC DRUGS

57. VIDEO
• Acute Coronary syndrome

60. FIBRINOLYTIC DRUGS
First Generation
• Streptokinase
Second Generation
• Alteplase (rt-PA)
• Reteplase
• Tenecteplase

62. Streptokinase
• Streptokinase was discovered in 1933 from beta-hemolytic streptococci
• It is non-fibrin specific, i.e. activates both circulating as well as fibrin bound plasminogen
• Depletes circulating fibrinogen and predisposes to bleeding
• Cannot be used second time due to neutralization by antibodies generated in response to the earlier
dose(Molecular mimickry)

63. Streptokinase
• Common adverse effects of all the thrombolytic drugs is bleeding complications related to systemic
fibrinogenolysis and lysis of normal hemostatic plugs.
• The bleeding is often noted at a catheterization site, although gastrointestinal and cerebral
hemorrhages may occur
• Patients who have experienced trauma injury or who have a history of cerebral hemorrhagic stroke are
not usually administered thrombolytics. Re-thrombosis can occur following thrombolysis, and therefore
anticoagulants such as heparin are usually co-administered, and continued after thrombolytic therapy
for a period of time.
Adverse Effects and Contraindications

64. Tenecteplase
• Only fibrinolytic agent that can be injected i.v. as a single bolus dose over 10 sec
• Possible to institute fibrinolytic therapy immediately on diagnosis of STEMI, even during transport
of the patient to the hospital.

65. Clinical uses of fibrinolytics
Acute myocardial infarction
Deep vein thrombosis (DVT)
Pulmonary embolism (PE)
Stroke

66. ANTIFIBRINOLYTIC DRUGS
Uses For prevention/control of excessive bleeding due to:
• Fibrinolytic drugs.
• Cardio-pulmonary bypass surgery.
• Tonsillectomy, prostatic surgery, tooth extraction in haemophiliacs.
• Menorrhagia, especially due to IUCD.
• Recurrent epistaxis, hyphema due to ocular trauma, peptic ulcer.
• Binds to the lysine binding site on plasminogen and prevents its combination with fibrin leading to
fibrinolysis

67. ANTIPLATELET DRUGS
(Antithrombotic drugs)
• These are drugs which interfere with platelet function and are useful in the prophylaxis of
thromboembolic disorders.
• In arteries, platelet mass is the main constituent of the thrombus. Antiplatelet drugs are,
therefore, more useful in arterial thrombosis, while anticoagulants are more effective in venous
thrombosis.
• The major role of antiplatelet drugs in clinical practice is to prevent the adverse clinical
sequelae of thrombosis in atherosclerotic arteries to the heart (acute coronary syndromes
[ACS]), brain (ischaemic stroke), and limbs (intermittent claudication and rest pain); and
thrombosis of stagnant blood in veins

73. P2 Y12 receptor blocker
• Ticlopidine
• Clopidogrel
• Prasugrel
• Ticagrelor
GP IIb IIIa
antagonists
• Abciximab
• Eptifibatide
• Tirofiban
Throboxane synthesis
inhibitor
• Aspirin
Platlet cAMP enhancer
• Dipyridamole
ANTIPLATELET DRUGS
(Antithrombotic drugs)

75. ASPIRIN
• Inactivates acetylates the enzyme COX1 and TX-synthase
• TXA2 formation is suppressed at very low doses and till fresh platelets are formed. Thus, aspirin
induced prolongation of bleeding time lasts for 5–7 days.
• Effect of daily doses cumulates and it has been shown that doses as low as 40 mg/day have some
effect on platelet aggregation.
• At low doses (75–150 mg/day or 300 mg twice weekly), TXA2 formation by platelets is selectively
suppressed, whereas higher doses (> 900 mg/day) may decrease both TXA2 and PGI2 production.

76. Clopidogrel
• Irreversibly blocks the P2Y12 type of purinergic receptor on the surface of platelets
• Combination of clopidogrel and aspirin is synergistic in preventing ischaemic episodes
• This ‘dual antiplatelet therapy’ (DAPT) is also utilized for checking restenosis of stented
coronaries.
Prasugrel
• Used in ACS as well as when strong antiplatelet action is required significant reduction in stent
thrombosis
• Recovery of platelets from prasugrel action takes longer (7 days) than with clopidogrel (5 days).

77. Glycoprotein (GP) IIb/IIIa receptor antagonists
Abciximab
• Block the key receptor involved in platelet aggregation
• Used only in patients with ACS and to cover PCI or coronary artery bypass grafting (CABG)
• Given along with aspirin + heparin during PCI it has markedly reduced the incidence of restenosis,
subsequent MI and death.
• Used in unstable angina and as adjuvant to coronary thrombolysis/ PCI with stent placement

81. Uses of antiplatelet drugs in clinical practice
Coronary artery disease
• It is recommended that aspirin 75–150 mg/day be given to all individuals with evidence of coronary
artery disease
• Continued aspirin/clopidogrel prophylaxis in post-MI patients clearly prevents reinfarction and
reduces mortality.

83. Uses of antiplatelet drugs in clinical practice
Acute coronary syndrome
• ACS (Acute coronary syndrome) comprise of a range of acute cardiac ischaemic states from unstable
angina (UA) to non-ST elevation myocardial infarction (NSTEMI) to STEMI

84. Uses of antiplatelet drugs in clinical practice
Cerebrovascular disease
• Aspirin has reduced the incidence of TIAs and of stroke in patients with TIAs.
• Aspirin or clopidogrel is given to all patients of TIAs who are not to be treated with anticoagulants

85. Uses of antiplatelet drugs in clinical practice
Prosthetic heart valves and arteriovenous shunts
• Antiplatelet drugs, used with warfarin reduce formation of microthrombi on artificial heart valves and the
incidence of embolism
• Antiplatelet drugs also prolong the patency of chronic arteriovenous shunts implanted for haemodialysis

86. Uses of antiplatelet drugs in clinical practice
Venous thromboembolism
• Anticoagulants are routinely used in DVT and PE

87. THANKS