ANTICOAGULANTS

Dr. D. K. BrahmaDepartment of Pharmacology

NEIGRIHMS, Shillong

Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

Fibrin polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affectedBy Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

Recall !

Why anticoagulants ?To reduce the coagulability of bloodBlood clots – ThrombusArterial 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 embolusVenous emboli can block arterioles in the lung and pulmonary

circulationThromboembolism

Available AnticoagulantsUsed in vivo:

1. Parenteral anticoagulants:– Indirect thrombin inhibitors: Heparin, Low molecular weight heparin,

Fondaparinux, Danaparoid– Direct thrombin inhibitors: Lepirudin, Bivalirudin

2. 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)

Heparin as PrototypeEndogenous - strongest organic acid present in the

BodyPresent in mast cells (MW – 75,000) – lungs, liver and

intestinal mucosaCommercially - from Ox lung and Pig mucosa

(slaughter house)Chemically, non-uniform mixture of straight chain

mucopolysaccharides with MW 10,000 to 20,000Carries 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

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

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

Heparin mechanism of action

Heparin

Antithrombin IIIThrombin

Heparin – Contd.• Adverse effects:

1. Bleeding due to overdose – haematuria is 1st sign2. Thrombocytopenia – aggregation of platelets3. 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

Low Molecular Weight Heparin (LMWH)

• 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– 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)

• 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

Interfered PT aPTT

IP N P

EP P N

CP P P

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

Oral Anticoagulants

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

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)

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

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

FIBRINOLYTICS

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– non-specific fibrinogen depletory – but less effect than newer ones in fibrinolysis

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

• Tenecteplase: genetically engineered, higher fibrin selectivity, not inactivated by PAI-1, can be injected over 10 seconds single bolus

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

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)

Antiplatelet Drugs (antithrombotic drugs)

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

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

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

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

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

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

Must Know

• Heparin, LMWH and Protamine sulfate• Warfarin• Fibrinolytics (Thrombolytics)• Antiplatelet Drugs – Aspirin, Dipyrydamole

and Clopidogrel

THANK YOU