Anti coagulants and anti platelets- mrcem

Anti coagulants and anti plateletsA discussion about the drugs

FACTOR NAME I Fibrinogen II Prothrombin III Tissue factor or thromboplastin IV Calcium V Proaccelerin (Labile factor) VII Proconvertin (Stable factor) VIII Antihaemophilic factor A,

Antihaemophilic globulin

IX Antihaemophilic factor B, Plasma thromboplastin component, Christmas factor

X Stuart-Prower factor

XI Plasma thromboplastin antecedent, Haemophilia C, Rosenthal syndrome

XII Hageman factor XIII Fibrin stabilising factor,

Laki-Lorand factor

.

Clotting Cascade

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

Consequences of thrombus

consequences

angina Myocardial infarction stroke

Deep venous

thrombosis

Anticoagulant Therapy

Treatment of thrombus

Prevent ThrombosisAnticoagulants

Antiplatelets

Removing the occlusionThrombolysis

Coronary angioplasty

VasodilationNitrates

CCB

Antithrombotic drugs

Fibrinolytics


Fibrinolytics


Fibrinolytics


Fibrinolytics

Anti coagulants

History of Anticoagulants• Heparin was discovered in 1915 by McLean• Warfarin has been the drug of choice for the

prevention and treatment of arterial and venous thrombotic disorders for more than 60 years

• It was initially marketed as a pesticide against rats and mice, and is still popular for this purpose

Anti coagulants• Direct thrombin inhibitors• Indirect thrombin inhibitors

DIRECT THROMBIN INHIBITORS

· Hirudin – Lepirudin· Bivalirudin· Argatroban· Melagatran· Ximelagatran (oral)· Dabigatran (oral)

INDIRECT THROMBIN INHIBITORS

• Heparin• LMWH – Enoxaparin, dalteparin• Fondaparinaux• Rivaroxiban (1st oral factor Xa inhibitor)

Classification

Parenteral

• Heparin• Heparinoids• Agratroban• Hirudins• Epoprostenol• Fondaparinux

Oral

• Warfarin• Acenocoumarol• Phenindione

Anti coagulants- uses• Prevent thrombus formation• Prevent extension of an existing thrombus• Used in venous thrombus

Heparin-Plus and minusUnfractionated heparin• Short duration of action• Bioavailability less (22-40%)• Onset immediate(iv), s/c (2-4hr)• ½ life 60-90 mins• Continuous iv or intermittent s/c

infusion• Can be withdrawn easily in case of

any complication• Daily aPTT monitoring

LMWH• Longer duration• Bioavailability more (>90%)• Onset (3-5hrs)• ½ life 4.5 hrs• Titrated dose• Effect will remain even after

withdrawal• Weekly monitoring

Heparin

• Mechanism for low dose: Inactivates factor Xa and inhibits conversion of prothrombin to thrombin

• Mechanism for high dose: Inactivates factors IX, X, XI, and XII and thrombin and inhibits conversion of fibrinogen to fibrin

• Also inhibits activation of factor VIII

Mechanism of action

Prophylaxis•5000 units SC q8-12hr, OR•7500 units SC q12hr

Treatment•80 units/kg IV bolus, THEN continuous infusion of 18 units/kg/hr, OR •5000 units IV bolus, THEN continuous infusion of 1300 units/hr, OR•250 units/kg (alternatively, 17,500 units) SC, THEN 250 units/kg q12hr

the heparin needs to be continued for at least 5 days and until theINR is 2 for at least 24 hours

DVT / PE Uses

Acute Coronary Syndromes

PCI•Without GPIIb/IIIa inhibitor: Initial IV bolus of 70-100 units/kg (target ACT 250-300 sec) •With GPIIb/IIIa inhibitor: Initial IV bolus of 50-70 units/kg (target ACT >200 sec)

STEMI•Patient on fibrinolytics: IV bolus of 60 units/kg (max: 4000 units), THEN 12 units/kg/hr (max 1000 units/hr) as continuous IV infusion•Dose should be adjusted to maintain aPTT of 50-70 sec

Unstable Angina/NSTEMI•Initial IV bolus of 60-70 units/kg (max: 5000 units), THEN initial IV infusion of 12-15 units/kg/hr (max: 1000 units/hr)•Dose should be adjusted to maintain aPTT of 50-70 sec

Anticoagulation

Intermittent IV injection•8000-10,000 units IV initially, THEN 50-70 units/kg (5000-10,000 units) q4-6hr

Continuous IV infusion•5000 units IV injection, followed by continuous IV infusion of 20,000-40,000 units/24 hr

Catheter PatencyPrevention of clot formation within venous and arterial cathetersUse 100 units/mL; instill enough volume to fill lumen of catheter

ContraindicationsSevere thrombocytopeniaUncontrolled, active bleeding (except DIC)Conditions in which coagulation tests cannot be performed at appropriate intervals

CautionsAny risk factor for hemorrhage (eg, subacute bacterial endocarditis, blood dyscrasias, menorrhagia, dissecting aneurysm, major surgery, spinal anesthesia, hemophilia, GI ulcerative lesions, liver disease, impaired hemostasis)

Adverse effectHeparin-induced thrombocytopenia may occur (with or without thrombosis)

Mechanism of ActionLMWH; antithrombotic that inhibits factor Xa by increasing inhibition rate of clotting proteases that are activated by antithrombin III

Generally does not increase PT or PTT

LMWH

Deep Vein Thrombosis (Prophylaxis)

Abdominal surgery•40 mg SC qDay; initiate 2 hr preoperatively

Knee or hip replacement surgery•30 mg SC q12hr; initiate therapy 12-24 hr postoperatively and continued for 10 days or up to 35 days postoperatively or until risk of DVT has been significantly reduced or patient is on anticoagulant therapy

•For hip replacement surgery, may consider administering 40 mg SC qDay, initiated 9-15 hr preoperatively and continued for 10 days or up to 35 days postoperatively or until risk of DVT has been significantly reduced or patient is on anticoagulant therapy

Medical patients with restricted mobility•40 mg SC qDay; continue until risk of DVT has been significantly (6-11 days) reduced or patient is on anticoagulant therapy

Deep Vein Thrombosis (Treatment)Inpatient treatment•Acute DVT with or without PE, when administered in conjunction with warfarin sodium•1 mg/kg SC q12hr, OR 1.5 mg/kg SC qDay (administer at same time each day) Outpatient treatment•Acute DVT without PE, when administered in conjunction with warfarin sodium•1 mg/kg SC q12hr

Unstable Angina & Non-Q-Wave MIProphylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin1 mg/kg SC q12hr Regimen includes aspirin (100-325 mg/day PO)

Acute STEMI<75 years•Loading dose: 30 mg IV bolus once plus 1 mg/kg SC once; not to exceed 100 mg cumulative loading dose •Maintenance: 1 mg/kg SC q12hr

>75 years•No IV bolus•0.75 mg/kg SC q12hr•Not to exceed 75 mg/dose for first 2 doses only, followed by 0.75 mg/kg for remaining doses

With PCI•If last enoxaparin was given <8 hr before balloon inflation, no additional dosing is needed•If last enoxaparin was given 8-12 hr before balloon inflation, an IV bolus of 0.3 mg/kg should be administered •If PCI occurs >12 hr after last SC dose; use established anticoagulation therapy (full-dose unfractionated heparin or LMWH•Patient that has not received prior anticoagulant therapy: 0.5-0.75 mg/kg bolus dose

Contraindications

Active major bleeding, thrombocytopenia with antiplatelet antibody in presence of enoxaparin or heparin

Hypersensitivity to enoxaparin, heparin, pork products, or other ingredients

CautionsEpidural or spinal hemorrhage and subsequent hematomas reported with the use of enoxaparin

epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis

contraindications

Bleeding or hemophilia

hypertension

Thrombocytopenia or purpura

Hypersensitivity to heparin

Intracranial hemorrhage

Recent surgery

TB

GIT ulcer

Hepatic or renal disease

Use of digoxin

Mechanism of ActionProtamine that is strongly basic combines with acidic heparin forming a stable complex and neutralizes the anticoagulant activity of both drugs

PharmacokineticsHalf-life elimination: 7 minOnset: 5 min

Time Elapsed Since Heparin DoseDose of protamine (mg) to neutralize 100 units of heparin•<1/2 hr: 1-1.5 mg/100 units of heparin•30-120 min: 0.5-0.75 mg/100 units of heparin•>2 hr: 0.25-0.375 mg/100 units of heparin

Protamine sulphate

Mechanism of ActionAntithrombotic agent; inhibits factor Xa, which interrupts blood coagulation cascade and inhibits thrombin formaiton and thrombus development; generally does not increase prothrombin time (PT) or partial thromboplastin time (PTT)

AbsorptionBioavailability: 100%Peak plasma time: 2-3 hr

Fondaparinux

Deep Vein Thrombosis/Acute Pulmonary EmbolismTreatment

<50 kg: 5 mg SC once daily50-100 kg: 7.5 mg SC once daily>100 kg: 10 mg SC once daily

Administer for 5-9 days; up to 26 days administered in clinical trials

Prophylaxis>50 kg: 2.5 mg SC once daily for 5-9 days or up to 10 days following abdomonal surgery; for hip replacement, 11 days recommended and a minimum 10-14 days recommended for patients undergoing total hip or knee arthroplasty, or hip fracture surgery; administered for up to 35 days in some instances

Heparin-Induced Thrombocytopenia (Off-label)Prophylaxis of deep vein thrombosis (DVT) in patient with history of heparin-induced thrombocytopenia (HIT) until patient can switch to warfarin2.5 mg SC once daily

American College of Chest Physicians (ACCP) guidelines assign low evidence rating to treatment of HIT with fondaparinux and conclude that further studies evaluating its role in HIT treatment are needed

Mechanism of ActionInterferes with hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, as well as proteins C and S; S-warfarin is 4 times more potent than R-warfarinWarfarin depletes functional vitamin K reserves, which in turn reduces synthesis of active clotting factors, by competitively inhibiting subunit 1 of the multi-unit vitamin K epoxide reductase complex 1 (VKOR1)

AbsorptionOnset: 36-48 hrDuration: 2-5 daysPeak plasma time: 1.5-3 days

DistributionProtein bound: 99% (albumin)

Warfarin

Venous ThrombosisProphylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE)Initial dose: 2-5 mg PO/IV qDay for 2 days, OR 10 mg PO for 2 days in healthy individualsInitiate warfarin on day 1 or 2 of LMWH or unfractionated heparin therapy and overlap until desired INR, THEN discontinue heparinCheck INR after 2 days and adjust dose according to resultsTypical maintenance dose ranges between 2 and 10 mg/day

DVT and PE treatment•Initiate warfarin on day 1 or 2 of parenteral anticoagulation therapy (eg, LMWH or unfractionated heparin)•Overlap warfarin and parenteral anticoagulant for at least 5 days until desired INR (>2.0) maintained for 24 hours, then discontinue parenteral therapy

Stroke & ThromboembolismProphylaxis and treatment of systemic embolic complications (eg, stroke) associated with atrial fibrillation (AF)Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individualsTypical maintenance dose ranges between 2-10 mg/dayCardiac Valve ReplacementProphylaxis and treatment of thromboembolic complications associated with cardiac valve replacementInitial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individualsPost-Myocardial InfarctionReduction in the risk of death, recurrent MI, and thromboembolic events (eg, stroke, systemic embolization) after MIInitial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

ContraindicationsPregnancy, except in women with mechanical heart valvesHemorrhagic tendencies or blood dyscrasiasRecent or contemplated CNS or eye surgery or traumatic surgery resulting in large open surfacesBleeding tendencies associated with CNS hemorrhage, cerebral aneurysms, dissecting aorta, pericarditis and pericardial effusions, bacterial endocarditis, and active ulceration or overt bleeding of the GI, GU, or respiratory tractThreatened abortion, eclampsia, and preeclampsiaUnsupervised patients with conditions associated with potential high level of noncompliance (eg, dementia, alcoholism, psychosis)Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleedingMajor regional or lumbar block anesthesiaKnown hypersensitivityMalignant hypertension

CautionsLower doses may be warranted in the elderly, debilitated patients, malnutrition, CHF, or liver disease

The future for anticoagulants• Factor Xa is an

attractive target for the design of new oral anticoagulants because of the unique role factor Xa plays in the coagulation cascade as a connection between the extrinsic and intrinsic pathways

ANTIPLATELETS

• Aspirin• ADP receptor antagonists – clopidogrel,

ticlopidine• GP IIB/IIIA inhibitors – Abciximab, Eptifibatide,

Tirofiban• Dipyridamole• Cilostazol

Uses1.Prophylaxis of venous thrombosis.2.Transient cerebral ischemic attacks.2.Following coronary artery bypass grafting.3.Prevention of myocardial infarction.4.Following coronary artery angioplasty.5.Prosthetic heart valves.6.Chronic disseminated intravascular coagulation.

The role of platelets




Aspirin ( Acetylsalicylic Acid ) Mechanism of Action1. Irreversible inhibition of cyclooxygenase enzyme via acetylation.2. Small dose inhibits thromboxane synthesis in platelets (TXA2) But not prostacyclin (PGI2) synthesis in endothelium (larger dose).

Bioavailability: 80-100%

Onset: PO, 5-30 min; PR, 1-2 hr

Duration: PO, 4-6 hr; PR, >7 hr

Metabolized by liver via microsomal enzyme systemExcretion: Urine (80-100%), sweat, saliva, feces

Acetylsalicylic acid – mechanism of action



Acute Coronary SyndromeFor use as adjunctive antithrombotic effects for ACS (ST-segment elevation myocardial infarction [STEMI], unstable angina [UA]/non-ST-segment elevation myocardial infarction [NSTEMI])

Acute symptoms•160-325 mg PO; chew nonenteric-coated tablet upon presentation (within minutes of symptoms)•If unable to take PO, may give 300-600 mg suppository PR

Maintenance (secondary prevention)•75-81 mg PO qDay indefinitely (preferred dose); may give 81-325 mg/day•Regimen may depend on coadministered drugs or comorbid conditions

Percutaneous transluminal coronary angioplasty•Adjunctive aspirin therapy to support reperfusion with primary PCI (with or without fibrinolytic therapy)•Preoperative dose: 162-325 mg PO before procedure•Maintenance: 81 mg PO qDay indefinitely (preferred dose) may give 81-325 mg/day

Pain & Fever325-650 mg PO/PR q4-6hr PRN

Ischemic Stroke & Transient Ischemic Attack50-325 mg/day PO within 48 hours of stroke or TIA, then 75-100 mg/day PO

Osteoarthritis/Rheumatoid Arthritis /Spondyloarthropathy Up to 3 g/day PO in divided doses

Colorectal Cancer (Off-label)Prophylaxis600 mg/day PODecreases risk of developing hereditary colorectal cancer (ie, Lynch syndrome) by 60% if taken daily for at least 2 years

ContraindicationsHypersensitivity to aspirin or NSAIDs; aspirin-associated hypersensitivity reactions include aspirin-induced urticaria (HLA-DRB1*1302-DQB1*0609 haplotype), aspirin-intolerant asthma (HLA-DPB1*0301)Allergy to tartrazine dye Absolute•Bleeding GI ulcers, hemolytic anemia from pyruvate kinase (PK) and glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemophilia, hemorrhagic diathesis, hemorrhoids, lactating mother, nasal polyps associated with asthma, sarcoidosis, thrombocytopenia, ulcerative colitis

Relative•Appendicitis, asthma (bronchial), chronic diarrhea, bowel outlet obstruction (for enteric-coated formulations), dehydration, erosive gastritis, hypoparathyroidism

CautionsAnemia, GI malabsorption, history of peptic ulcers, gout, hepatic disease, hypochlorhydria, hypoprothrombinemia, renal impairment, thyrotoxicosis, vitamin K deficiency, renal calculi, ethanol use (may increase bleeding)Discontinue therapy if tinnitus developsShould be taken with food or 8-12 oz of water to avoid GI effectsNot indicated for children with viral illness; use of salicylates in pediatric patients with varicella or influenza like illness is associated with increased incidence of Reye syndrome

Clopidogrel (ADP pathway inhibitor)

Mechanism of Action

Inhibits the binding of ADP to its platelet receptor by irreversibly modifying the platelet ADP receptor.

AbsorptionBioavailability: >50%Onset: 2 hrPeak serum time: 0.75 hrPeak plasma concentration: 3 mg/L

MetabolismMetabolized in liver by hepatic CYP450 enzymes

EliminationHalf-life: 6 hr (parent drug); 30 min (active metabolite)Excretion: Urine (50%), feces (46%)

ADP-receptor antagonists – mechanism of action




Acute Coronary SyndromeUnstable angina, non-ST-segment elevation MI (NSTEMI): 300 mg loading dose, then 75 mg/day PO for up to 12 months; administer indefinitely if used in combination with aspirin 75-100 mg/dayST-segment elevation MI (STEMI): 75 mg/day PO in combination with aspirin 162-325 mg/day and then 81-162 mg/day

<75 years•300 mg loading dose followed by 75 mg for 14 days up to 12 months (if no bleeding)•Concomitant therapy with aspirin: Administer in combination with aspirin 75-325 mg qDay with or without thrombolytics

>75 years•No loading dose•75 mg for 14 days up to 12 months (if no bleeding)

Recent MI, Stroke, or Established Peripheral Arterial Disease75 mg PO qDay; recommended as alternative to aspirin or concomitantly with aspirin if patient not at increased risk for bleeding but at high risk for cardiovascular disease

Coronary Artery Disease75 mg PO qDay

Cardioembolic StrokeProphylaxis if patient not candidate for oral anticoagulation75 mg/day PO

Carotid Artery Stenting (Off-label)300 mg PO plus aspirin 81-325 mg for 1 dose on day before carotid artery stenting (CAS), then 75 mg/day PO plus aspirin 81-325 mg/day for at least 30 days after CAS Alternative: 300-600 mg PO once, then 75 mg/day for 4 days before CAS in combination with aspirin 81-325 mg/day

ContraindicationsHypersensitivityActive pathologic bleeding (eg, peptic ulcer, intracranial hemorrhage)

CautionsUse with caution in patients with bleeding or platelet disordersMay increase risk of major hemorrhage in patients with recent lacunar stroke

CYP2C19 inhibition & poor metabolizers

DipyridamoleMechanism of ActionPhosphodiestrase inhibitor cAMP in the blood platelets inhibition of platelet aggregation.

AMP cAMP degradation of cAMP

Non-nitrate coronary vasodilatorInhibition of RBC uptake of adenosine thereby inhibiting platelet reactivityPhosphodiesterase inhibition increasing cAMP in platelet, ORInhibition of Thromboxane A2 formation (vasoconstrictor and a stimulator of platelet activation)

Dipyridamole – mechanism of action



Thromboembolism Prophylaxis Post-Cardiac Valve Replacement75-100 mg PO q6hr as adjunct to warfarin

Adjunct to Thallium Myocardial Perfusion Imaging (Off-label)Adjusted according to body weight; recommended 0.142 mg/kg/min IV infusion over 4 minutes; not to exceed 60 mg

ContraindicationsHypersensitivityThrombocytopenia

CautionsFDA approval for chronic angina withdrawn

uses

GPIIb/IIIa-receptor antagonists – mechanism of action





fibrinolytics

Thrombolytic drugs – mechanism of action




The end

Health & Medicine

Anti coagulants and anti platelets- mrcem