BLOOD FORMING AGENTS

Clinical Thrombosis> 2.5 million cases of deep venous thrombosis (DVT) annually > 600.000 cases of pulmonary embolism (PE) per year> 50.000 deaths per year from PE> 11.000 post surgical PE deaths per year

Anti Platelet Drugs

DrugMechanismUsesAspirinPermanently inhibits COX-1 and COX-2CAD (coronary artery disease) Stroke-TIAs (transient ischemic attack)

NSAIDsReversibly inhibits COX-1LimitedDipyridamoleInhibits PDE; increases cAMPTIAsTiclopidineClopidogrelInhibits ADP; active metaboliteTIAs; StrokeCAD; PVD (peripheral vascular disease)

INHIBITORS OF PLATELET AGGREGATION

Platelets inhibitors - ASADaily dose - 80-100 mgKardiomagnil

ANTIPLATELET THERAPYAspirin Indications1)Stroke, TIA (transient ischemic attacks)2)MI, recurrent MI3)Unstable angina4)CABG potency (coronary artery bypass graft )

TICLOPIDINE 1)Interferes with platelet-fibrinogen binding 2)Exerts its action for the life of the platelet3)May prolong bleeding timeUseful for coronary artery stents and CVA (cerebrovascular accident )5)Methylprednisolone may reverse its effect6)Associated with TTP (thrombocytopenic purpura), neutropenia, and diarrhea

CLOPIDOGRELInterferes with GP IIb/IIIa (Glycoprotein IIb/ IIIa ) binding site 2)Exerts its action for the life of the platelet3)May prolong bleeding time4)Indicated for prevention of MI, CVA (cerebrovascular accident), and vascular death5)Fewer side effects than ticlopidine6)Dose: 75 mg daily

Abciximab (ReoPro)Human-mouse monoclonal antibodies Binds to GP (glycoprotein) IIb/IIIa receptor on plateletsHalf-life 10 min.May block receptor for 10 daysIndicated for prevention of closure of coronary vessels after angioplastyMay cause thrombocytopeniaUsed with heparin and ASA

Antiplatelet therapy

Mechanism of heparin action 5513 ant thrombin thrombin prothrombinase (Stuart-Prover factor)10

IV or SC administration onlyHEPARIN

HEPARIN (Indications)Full Dose: 5000 U or 80 U/kg IV bolus, followed by 1200-1600 U/hr adjusted to therapeutic range 1)Acute deep venous thrombosis 2)Pulmonary emboli 3)Unstable angina and myocardial infarctionLow Dose: 5000 U sq q12 h 1)Postoperative prophylaxis of any major abdominal, thoracic, gynecologic, or orthopedic procedure 2)Immobilized medical patients >40 yrs. with CHF, CVA, malignant disease 3)Prophylaxis for underlying hypercoagulable stateOther Dose: 1)Extracorporeal bypass 2)Hemodialysis 3)After thrombolytic therapy

HEPARIN (Contraindications)1)Thrombocytopenia2)Aspirin or alcohol use3)Hepatic or renal disease4)Other platelet dysfunction5)GI bleeding6)Tumors

HEPARIN (Side Effects)1)Major side effect is bleeding2)Osteoporosis with prolonged use3)Thrombocytopeniaw

HEPARIN-INDUCED THROMBOCYTOPENIA 1)Occurs in 2-5% of patients receiving standard heparin by immune mechanismMay occur with minute doses, including heparin flushesMore common with bovine than porcine heparinAsymptomatic thrombocytopenia can occur in 30-50% of pts who develop HIT antibodies ~20-50% of thrombocytopenic patients develop arterial or venous thrombosis that may be life threatening

LepirudinArgatroban HEPARIN-INDUCED THROMBOCYTOPENIA Alternative Anticoagulants- direct thrombin inhibitors

LOW MOLECULAR WEIGHT HEPARIN

1) Molecular weight 3,000- 7,000 D2)Inhibits factor Xa rather than thrombin3)Factor Xa assay used for monitoring 4)Administered subcutaneously 2 times/d5)Probably less antigenic than standard heparin6)Recommended for prophylaxis and treatment

LOW MOLECULAR WEIGHT HEPARIN1) PT, APTT not usually prolonged2) May be monitored with anti-factor Xa assay

jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

LOW MOLECULAR WEIGHT HEPARINSggggggggggggggggggg

Indications for and Contraindications to Parenteral Anticoagulant Agents

Anticoagulant AgentClassApproved & Appropriate IndicationsContraindicationUnfractionated heparin

Enoxaparin(Lovenox)

Dalteparin(Fragmin)

Tinzaparin(Innohep)Antithrombin III inhibitor

Low-molecular-weight heparinLow-molecular-weight heparin

Low-molecular-weight heparinTreatment of venous thromboembolism or unstable angina; used when rapid reversal is importantProphylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable anginaProphylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable anginaProphylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism?Prophylactic treatment

Regional anesthesiaPregnancy

Prosthetic Heart ValvesRegional anesthesia

Regional anesthesia

Heparin-Antibiotic Interactions

The cephalosporins- cefamandole, cefotetan, and cefoperazone, contain an N-methylthiotetrazole (NMTT) side chain. This NMTT group can:

- Dissociate from the parent antibiotic in solution or in vivo and competitively inhibit vitamin K action, leading to prolongation of the prothrombin time and bleeding.

- This side chain is also associated with a disulfiram-like reaction to alcohol.

ANTICOAGULANTS OF INDIRECT ACTIONCOUMARIN (Description) 1)Isolated by Link in 1939 after previous observation that cattle developed bleeding disorder after ingestion of spoiled clover2)Is 4-hydroxycoumarin compound, similar in structure to vitamin K3)Administered p.o., rapid GI absorption4)Crosses placenta easily (complications!)5)Interacts with a variety of drugs

LIVER

COUMARIN (Actions)1) Blocks the carboxylation of the vitamin K dependent clotting proteins, factors II, VII, IX, and X, maintaining them in their inactive forms2) Blocks the anticoagulant proteins C and S 3) Onset 18-48 hours

COUMARIN Laboratory1)Prolongs the PT and APTT2)PT and Prothrombin index -used for monitoring

Prothrombin index INTERNATIONAL NORMALIZED RATIO (INR)

INR = PATIENT PT CONTROL PT

Decrease no less than 50 %

COUMARIN Side Effects1)Hemorrhage2) Fetal abnormalities3)Skin necrosis with deficiencies of proteins C or S usually on 3rd to 8th day of therapy

COUMARIN InteractionsPOTENTIATORS :PhenylbutazoneCimetidineOmeprazoleAmiodaroneAnabolic steroidsANTAGONISTS :BarbituratesRifampinPenicillinsAntacids

Pharmacodynamics of fibrinolytic drugsAfter introduction into organism they cause lyses of fresh (24-72 hours) thrombi in arteries, veins, cavitiesThe most effective during the first 2-3 hours after initiation of thrombosis

Thrombin only topical !!!

HAEMOSTATICS with systemic actionFibrinogen, Calcium chloride, vitamin , Vikasolum

INHIBITORS OF FIBRINOLYSISof direct action (Contrikal, Trasilol, Gordox)of indirect action (Ac aminocapronicum, Ac. tranexamicum, Amben)

EthamsilateStabilizes the walls of vessels

Urtica (Nettle)

Viburnum (Snow ball, Water elder)

Arnica (arnica)

Polygonum hydropiper (Water pepper)

Hippocastanum (Aescusan)(Horse chestnut)

Ginkgo biloba(Maidenhair-tree) Tanakan

DRUGS EFFECTING HAEMOPOESIS

Food products with iron

MeatSoybeansDry smoked plumsSpinachDry apricotsBuckwheatRiceBreadFruits of pomegranate Iron from animal products absorbs much more better than from plants (22 % and 1 %)

************