Indications of anticoagulant therapy

• Established venous thromboembolism

• Prophylaxis of venous thrombosis and pulmonary embolism

• Prosthetic heart valve • Rheumatoid mitral

valvular disease • Myocardial infarction

Contraindications • Pre existing bleeding

disorder• Stroke within 3 weeks or

neural / ocular surgery• Severe uncontrolled

hypertension• Active peptic ulcer , IBS• Renal failure • Liver cirrhosis • Pregnancy ( warfarin)

Heparin• Mucopolysachharide

Heparin is a powerful and instantaneously acting anticoagulant ,effective both invivo and in vitro.It is not absorbed by mouth and is usually given by intravenous or sometimes by subcutaneous injection.

MECHANISM OF ACTIONS

Heparin acts indirectly by binding to antithrombin III(AT III ,a serine proteinase inhibitors).The heparin AT III complex then binds to clotting factors and inactivates them ,thus by inhibits coagulation.

• Inhibits factor II, VII, IX, X, XI, XII• Prevents conversion of prothrombin to thrombin• Prevents conversion of fibrinogen to fibrin• Decrease platelet aggregation at high dose

Effects: • Anticoagulant• Antiplatelet• Lipemia clearing ( releasing lipoprotein lipase)

• Pharmacokinetics • Route : IV/SC• Onset of action : immediate ( within 10-15

mins )• Plasma half life : 40-90 mins • Metabolism : liver • Excretion : kidney

USES• Disseminated intravascular coagulation• Deep vein thrombosis• Pulmonary embolism• Postoperative or after myocardial surgery• Cardipulmonary bypass machines ( extra corporeal devices eg dialysis)• Thrombophlebitis • To reduce frequency of arterial embolism in patient with atrial fibrillation, mitral

stenosis or prosthetic heart valves • Prevention of clotting during

– Blood transfusion– Hemodialysis– Blood sampling for lab analysis Safe drug during pregnancy

ADVERSE EFFECTS• Hemorrhage• Hypersensitivity :

Chills,fever,urticaria,anaphylactic shock

• Thrombocytopenia• Transeint but reversible alopecia • Osteoporosis• Neuropathy • Inhibition of aldosterone secretion• Slowing of wound healing • Depression of cell mediated

immunity

CONTRAINDICATIONS• Hypersensitive patients• Patients having bleeding

disorders ( thrombocytopenia, hemophilia)

• Intracranial hemorrhage • Ulcerative lesions of GIT• Threatened abortion • Active tuberculosis • Alcoholics• Ocular and neurosurgery, • lumbar puncture

DOSES• IV bolus dose : 5,000-10,000 U

every 4-6 hours • Child dose : 50-100U/kg• Infusion is best given via a

syringe pump at the rate of 25000-30000 units in 24hrs following an initial bolus of 5000 units.If a pump is not available the heparin can be added to 1litre of saline or 5% dextrose and given as an infusion.

• To prevent thrombosis :5000 units in 0.2ml subcutaneously twice daily.

UNITS 1 Unit = amount of heparin that

prevents 1 ml of citrated sheep plasma from clotting for 1 hour after additon of 0.2 ml of 1% calcium chloride solution.

Heparin sodium 1 mg = 120-140U

Monitoring of heparin dose : Blood partial thromboplastin time with kaolin (PTTK) or aPTT . It should increase by 2.5 -3.5 times with heparin

Heparinisation

1) Continuous intravenous infusion via an infusion pump:

– Initial loading dose : 5000-10000 units – Continuous infusion : 900 units / hour – PTTK should be maintained at 2.5-3.5 times

control2) Intermittent intravenous administration:– Heparin : 75-100 units /kg every 4 hours 3) Subcutaneous administration ( low dose )– Heparin : 5000 units every 8 or 12 hours

Low molecular weight heparins • Selectively inhibit factor Xa with little effect on IIa• Better subcutaneous bioavailability• Advantages

– more predictable pharmacokinetic profile.– therapy may be provided in the outpatient setting– lower incidence of heparin-induced thrombocytopenia– lower risks of bleeding and osteopenia

• Once daily sc – Enoxaparin– Reviparin– Nadroparin– Dalteparin– Pamparin– Ardeparin

Heparin antagonist: protamine sulfate

• Strongly basic , low molecular weight protein• 1 mg needed for every 100 U of heparin• Rapid iv injection but rate should not exceed

50 mg in any 10 min period .

Other parenteral anticoagulants

• Lepirudin• Bivalirudin• Argatroban• Danaparoid• Drotrecogin Alfa

Oral anticoagulants

Warfarin and its congeners acts as anticoagulant only in vivo not in vitro.it is an oral anticoagulant.Unlike heparin, the anticoagulant effects of warfarin are not observed until 8-12 hours of drug administration.the anticoagulants effects of warfarin can be overcome by the administration of vitamin K.

MECHANISM OF ACTION

It acts indirectly by interfering with the synthesis of vitamin K dependent clotting factors in the liver. They interfere with regeneration of active hydroquinone which carries out gamma carboxylation of glutamate residues of prothrombin and factors VII, IX, and X.

• Inhibits Vit K epoxide reductase

• USES– Deep vein thrombosis– Pulmonary embolism– Myocardial infarction– Unstable angina – Frost bite – Acute gangrene – Cerebrovascular disease– Atrial fibrillation

ADVERSE EFFECTS– Bleeding– Hematuria– Bleeding in GIT– Intracranial or other internal

hemorrhages– Skin rashes / transient purpura – Drug fever – Jaundice– Purple toe syndrome – Congenital bony abnormality in

children ( if given in pregnancy )

Effects of warfarin on pregnancy

• Teratogenecity – Bony deformity – Nasal hypoplasia – CNS abnormality

• Abortion• Foetal and neonatal hemorrhage • Intrauterine death of the foetus

CONTRAINDICATIONS• Should not be used during pregnancy• Recent trauma , head injury • Active internal bleeding ( eg active ulceration)• Severe hyeprtension• Major surgery • Pre-existing bleeding disorders • Severe renal and hepatic disease

DOSEWarfarin sodiumInitial dose is 10-15mg ,maintenance dose 2-10mg daily for 4-7days

• Factors enhancing effect:– Malnutrition,

malabsorption, prolonged antibiotic therapy

– Liver diseases – Chronic alcoholism – Hyperthyroidism– newborn

• Factors decreasing effect – Pregnancy – Nephrotic syndrome – Genetic warfarin

resistance – Drugs : enzyme inducers (OCP)

Monitoring of oral anticoagulant therapy

INR ( international normalised ratio) :

Prothrombin time ratio ( test/ control) based on human thromboplastin . Optimum range should be 2.5-3.5 times normal for effective anticoagulant effect.

i) A coagulation screen and platelet count is done before starting treatment ii) Transfusion with fresh blood is required if blood loss has been excessive. ii) The dose of oral anticoagulant must be individualized by repeated measure of

prothrombin time

• Antidote: – Immediate antagonism : plasma concentrated

with vit K dependent clotting factors ( II, VII, IX , X)– Delayed antagonism by Inj Vitamin K ( I/ V)

Hemostatic agents / coagulants

1) Fresh whole blood or fresh frozen plasma

2) Vit K – K1 (from plants, fat soluble ) :

phytonadione ( phylloquinone )

– K2 ( produced by bacteria ) : menaquinone

– K3 ( synthetic) • Fat soluble : menadione ,

acetomenapthone • Water soluble : menadione

sodium bisulfite , menadione sod

diphosphate

3) Miscellaneous :– Fibrinogen – Antihemophilic factor – Adrenochrome – Monosemi carbazone – Rutin – Ethamsylate

4) Local hemostatics (styptics):– Thrombin– Fibrin– Gelatin foam – Russel viper venom– Vasoconstrictors– Astringents

Vitamin K• normal physiological

function: to promote the biosynthesis of the g-carboxy-glutamate (Gla) forms of factors II (prothrombin), VII, IX, and X, anticoagulant proteins C and S.

• Vitamin K, as KH2, the reduced vitamin K hydroquinone, is an essential cofactor for g-glutamyl carboxylase

minimum daily requirement

• 0.03 mg/kg of body weight

DEFICIENCY• can result from

inadequate intake, absorption, or utilization of the vitamin,

• or action of a vitamin K antagonist

• increased tendency to bleed• Ecchymoses, epistaxis,

hematuria, gastrointestinal bleeding, and postoperative hemorrhage are common

• intracranial hemorrhage may occur. Hemoptysis is uncommon.

• fetal warfarin syndrome may be related to a deficiency of the vitamin.

• deficits in bone mineral density and fractures;

• menadione and its derivatives cause hemolytic anemia and kernicterus in neonates, especially in premature infants

Uses• correct the bleeding

tendency or hemorrhage associated with its deficiency.

• Oral Anticoagulant overdose

• Hypoprothombinemia prophylaxis

Toxicity

• Rapid iv injection : flushing ,breathlessness , hypotension, and chest constriction

• Menadione can cause hemolysis , so not used

Fibrinolytics / thrombolytics

• Urokinase• Streptokinase• Alteplase – Recombinant tissue

plasminogen activator)

Streptokinase • It is a streptococcal exotoxin ( beta hemolytic streptococci group C) MECHANISM OF ACTIONS

– It combines with circulating–plasminogen-liberating plasmin which breaks down fibrin

– No intrinsic enzymatic activity but forms a stable complex with plasminogen . This complex then converts uncomplexed plasminogen to active plasmin which causes hydrolysis of fibrin plugs .

– Plasmin catalyses degradation of fibrinogen as well as clotting factors V and VII

USES– Pulmonary embolism – Peripheral arterial occlusion– Venous thrombosis– Lysis of coronary thrombosis(present use) in acute myocardial infarction– Clear occluded arterio venous cannula

• ADVERSE EFFECTS– Bleeding particularly at the sites of recent trauma.– Hypersensitive reactions– Anaphylaxis(especially when used second time in a patient)– Fever– Hypotension– Arrhythmias.

• PRECAUTIONS– It should not be used if patient has had previous streptokinase

within the last 12 months– Blood pressure should be monitored.

• CONTRAINDICATIONS– Surgery within 10 days including :

• Organ biopsy • Serious trauma

– Serious GIT bleeding within 3 months – History of hypertension– Hemorrhagic disorders – Cerebrovascular accident

• DOSE– For coronary thrombosis: 1.5 million units infused over 1hr this may be

preceded by chlorpheniramine 10mg and hydrocortisone 100mg to reduce allergic reactions. This is combined with 300mg aspirin ,which should be chewed before swallowing and followed by 150mg daily.

FIBRINOLYTIC INHIBITORS:• AMINOCAPROIC ACID• TRANEXAMIC ACID • PHYTOMENADIONE• APROTININ

• Aminocaproic acid (EACA)- chemically similar to the amino acid lysine• It competitively inhibits plasminogen activation It is rapidly absorbed

orally and is cleared from the body by the kidney. The usual oral dosage of EACA is 6 g four times a day. When the drug is administered intravenously, a 5 g loading dose should be infused over 30 minutes to avoid hypotension.

• Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose followed by 30 mg/kg every 6 hours

Anti thrombotic drugs / antiplatelet drugs

• Drugs interfering with platelet function:– Aspirin– Sulfinpyrazole– Ticlopidine – Eptifibatide– Tirofiban– Dextran-70– Dazaxiben – Dipyridamole – Epoprostenol– Clofibrate – Clopidogrel – Abciximab– Glycoprotein IIb/IIIa Inhibitors

Aspirin

• In platelets, the major cyclooxygenase product is thromboxane A2, a labile inducer of platelet aggregation and a potent vasoconstrictor.

• Aspirin blocks production of thromboxane A2 by acetylating a serine residue near the active site of platelet cyclooxygenase (COX-1), the enzyme that produces the cyclic endoperoxide precursor of thromboxane A2.

• 50 to 320 mg per day

Ticlopidine.

• Platelets contain two purinergic receptors, P2Y1 and P2Y12; both are GPCRs for ADP. The ADP-activated platelet P2Y1 receptor couples to the Gq-PLC-IP3-Ca2+ pathway and induces a shape change and aggregation. The P2Y12 receptor couples to Gi and, when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels of cyclic AMP and thereby less cyclic AMP-dependent inhibition of platelet that inhibits the P2Y12 receptor

• dose is 250 mg twice per day• common side effects are nausea, vomiting, and diarrhea.

The most serious is severe neutropenia .

Blood and plasma Volume expanders • High molecular weight substances that exert

colloidal osmotic pressure and when infused iv retain fluid in the vascular compartment.

• Substances:– Human albumin– Dextran – Degraded gelatin polymer – Hydroxyethyl starch ( HES) , hetastarch – Polyvinyl pyrrolidone (PVP)

• Desirable properties of plasma expanders :– Should exert osmotic pressure comparable to

plasma – Should remain in circulation and not leak out in

tissues or be too rapidly disposed – Should be pharmacodynamically inert – Should be non pyrogenic or antigenic – Should not interfere with grouping or cross

matching of blood – Should be stable , easily sterilizable , and cheap

Human albumin• Obtained from human pooled plasma • 100 ml of 20% human albumin equivalent to 400 ml of

fresh frozen plasma or 800 ml of whole blood .• Uses:

– Dehydration– Burns , hypovolemia – Shock – Acute hypoproteinemia – Acute liver failure – Dialysis

• Febrile reaction may occur • Expensive

Dextran • Polysachharide obtained from

sugar beat.• Dextran-70 ( MW- 70,000)- 6%

solution in dextrose or saline • Expands plasma volume for 24

hours and is excreted through kidney and oxidation.

• May interfere with blood grouping

• May cause allergic reactions : urticaria , itching , bronchospasm, hypotension and anaphylactic reaction.

• Can prolong bleeding time , so should not be given in hypofibrinogenemia, or thrombocytopenia

• Dextran-40 ( MW- 40,000) – 10% solution I dextrose or saline

• Reduces blood viscosity • Acts for a shorter

period and quickly eliminated through kidney

• Used in stroke , and for prophylaxis of deep vein thrombosis and pulmonary infarction.