Drugs used for treatment of coagulate disorders Drugs used for treatment of coagulate disorders

Clinical Thrombosis n > 2.5 million cases of deep venous thrombosis (DVT) per year n > 600,000 cases of pulmonary embolism (PE) per year n > 50,000 deaths per year from PE n > 11,000 post surgical PE deaths per year

ANTITHROMBOTIC THERAPY 1) Antiplatelet therapy 2) Anticoagulant therapy 3) Thrombolytic therapy

INHIBITORS OF PLATELET AGGREGATION

Anti Platelet Drugs DrugMechanismUses Aspirin Permanently inhibits COX-1 and COX-2 CADStroke-TIAs NSAIDs Reversibly inhibits COX-1 Limited Dipyridamole Inhibits PDE; increases cAMP TIAs TiclopidineClopidogrel Inhibits ADP PlatAg; active metabolite TIAs; Stroke CAD; PVD

Platelets inhibitors - ASA Daily dose mg Kardiomagnil

ANTIPLATELET THERAPY Aspirin Indications 1)Stroke, TIA (transient ischemic attacks) 2)MI, recurrent MI 3)Unstable angina 4)CABG potency ( coronary artery bypass graft )

TICLOPIDINE 1)Interferes with platelet-fibrinogen binding 2)Exerts its action for the life of the platelet 3)May prolong bleeding time 4) Useful for coronary artery stents and CVA (cerebrovascular accident ) 5)Methylprednisolone may reverse its effect 6)Associated with TTP (thrombocytopenic purpura), neutropenia, and diarrhea

CLOPIDOGREL 1)Interferes with GP IIb/IIIa ( Glycoprotein IIb/ IIIa ) binding site ( Glycoprotein IIb/ IIIa ) binding site 2)Exerts its action for the life of the platelet 3)May prolong bleeding time 4)Indicated for prevention of MI, CVA, and vascular death 5)Fewer side effects than ticlopidine 6)Dose: 75 mg daily

Abciximab (ReoPro) 1)Human-mouse monoclonal antibodies 2)Binds to GP IIb/IIIa receptor on platelets 3)Half-life 10 min. 4)May block receptor for 10 days 5)Indicated for prevention of closure of coronary vessels after angioplasty 6)May cause thrombocytopenia 7)Used with heparin and ASA

Ant platelet therapy

Recombinant Human Activated Protein C n Drotrecogin alfa (activated)- Xigris n Indicated for Severe Sepsis in Adults with Acute Organ Dysfunction with High Risk of Death n Reduction in Death as Primary End Point n Antithrombotic, Antiinfammatory, Profibrinolytic Properties n Serious Bleeding is Major Side Effect

Antithrombin III Inhibits the Following Serine Proteases n Coagulation n Factor XIIa n Factor XIa n Factor IXa n Factor Xa n Thrombin n Fibrinolysis n Plasmin Inhibitory activity against all these enzymes is substantially accelerated by heparin

HEPARIN (Description) 1)Discovered in 1916 by McLean; isolated from liver, thus the name heparin 2)Anionic glycosaminoglycan available as calcium or sodium salt, negative charge 3)Molecular weight 15,000 D (avg.) ( D) 4)Prepared from porcine intestinal mucosa and bovine lung 5)Does not cross placenta 6)Little interaction with other medications 7)IV or SC administration only 8)Reversible with protamine sulfate (1 mg/200 U heparin)

Heparin n About 1/3 of dose binds to AT III n To form the AT III:Heparin:Clotting Factor Complex- requires at least 18 saccarides except n Unique high affinity pentasaccaride heparin sequences catalyze inhibition of Xa by AT

HEPARIN (Action) 1) Binds to and potentiates antithrombin III antithrombin III 2)Heparin-antithrombin III complex inactivates thrombin (factor IIa) and factor Xa (Stuart-Prover) 3)Secondary effect against platelet function

Monitoring of Anticoagulant Therapy with Heparin Heparin s.q. – no monitoring required i.v. - APTT Activated Partial Thromboplastin Time i. v. - no less than 4 times daily or more frequent if PTT varies therapeutic goal – times normal control value (-30 sec)

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

Heparin n Pregnancy- YES

HEPARIN (Contraindications) 1 )Thrombocytopenia 2)Aspirin or alcohol use 3)Hepatic or renal disease 4)Other platelet dysfunction 5)GI bleeding 6)Tumors

HEPARIN (Side Effects) 1)Major side effect is bleeding 2)Osteoporosis with prolonged use 3)Thrombocytopenia

HEPARIN-INDUCED THROMBOCYTOPENIA 1)Occurs in 2-5% of patients receiving standard heparin by immune mechanism 2) May occur with minute doses, including heparin flushes 3) More common with bovine than porcine heparin 4) Asymptomatic thrombocytopenia can occur in % of pts who develop HIT antibodies 5) ~20-50% of thrombocytopenic patients develop arterial or venous thrombosis that may be life threatening

HEPARIN-INDUCED THROMBOCYTOPENIA 1) Usually appears 3-15 days after starting heparin, peak incidence day 8 2) Diagnosis is largely clinical despite availability of several tests used to attempt confirmation

1) Lepirudin 2) Argatroban HEPARIN-INDUCED THROMBOCYTOPENIA Alternative Anticoagulants

LEPIRUDIN 1)Recombinant form of hirudin 2)Highly specific direct thrombin inhibitor 3) Short half-life 1-2 hours 4) Monitored by APTT 5) Crosses placenta in rats, would not use in pregnancy at present 6) No antidote

LOW MOLECULAR WEIGHT HEPARIN 1) Molecular weight 3,000- 7,000 D 2)Inhibits factor Xa rather than thrombin 3)Factor Xa assay used for monitoring 4)Administered subcutaneously 2 times/d 5)Probably less antigenic than standard heparin 6)Recommended for prophylaxis and treatment

LOW MOLECULAR WEIGHT HEPARIN 1) PT, APTT not usually prolonged 2) May be monitored with anti-factor Xa assay

LOW MOLECULAR WEIGHT HEPARINS

Indications for and Contraindications to Parenteral Anticoagulant Agents Anticoagulant Agent Class Approved & Appropriate Indications Contraindication Unfractionated heparin Enoxaparin (Lovenox) Dalteparin (Fragmin) Tinzaparin (Innohep) Antithrombi n III inhibitor Low- molecular- weight heparin Treatment of venous thromboembolism or unstable angina; used when rapid reversal is important Prophylaxis in moderate- risk or high-risk patients, treatment of venous thromboembolism or unstable angina Prophylaxis in moderate- risk or high-risk patients, treatment of venous thromboembolism ?Prophylactic treatment Regional anesthesia Pregnancy Prosthetic Heart Valves Regional anesthesia

Heparin-Antibiotic Interactions n The cephalosporins- cefamandole, cefotetan, and cefoperazone, contain an N- methylthiotetrazole (NMTT) side chain. This NMTT group can: n - 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. n - This side chain is also associated with a disulfiram-like reaction to alcohol. n - Clinical bleeding has been less frequently reported with Cefotetan than with cefoperazone or cefamandole.

ANTICOAGULANTS OF INDIRECT ACTION

COUMARIN (Description) 1) Isolated by Link in 1939 after previous observation that cattle developed bleeding disorder after ingestion of spoiled clover 2)Is 4-hydroxycoumarin compound, similar in structure to vitamin K 3)Administered p.o., rapid GI absorption 4)Crosses placenta easily (complications!) 5)Interacts with a variety of drugs

COUMARIN (Actions) 1) Blocks the carboxylation of the vitamin K dependent clotting proteins, factors II, VII, IX, and X, maintaining them in their inactive forms 2) Blocks the anticoagulant proteins C and S 3) Onset – hours

PLASMA HALF-LIVES OF VITAMIN K DEPENDENT CLOTTING FACTORS Hours Factor II60 Factor II60 Factor VII6 Factor VII6 Factor IX24 Factor IX24 Factor X30 Factor X30 Protein C6 Protein C6 Protein S42 Protein S42

COUMARIN Laboratory 1)Prolongs the PT and APTT 2)PT and Prothrombin index -used for monitoring

Prothrombin index INTERNATIONAL NORMALIZED RATIO (INR) INR = PATIENT PT CONTROL PT CONTROL PT

COUMARIN Side Effects 1)Hemorrhage 2) Fetal abnormalities 3)Skin necrosis with deficiencies of proteins C or S usually on 3rd to 8th day of therapy

COUMARIN-INDUCED SKIN NECROSIS COUMARIN-INDUCED SKIN NECROSIS 1)Usually occurs on days 3-8 after initiation of Coumarin 1)Usually occurs on days 3-8 after initiation of Coumarin 2) More common in females (75%) 2) More common in females (75%) 3)Most common on the breast, buttocks, or extremities, occ. on penis in males 3)Most common on the breast, buttocks, or extremities, occ. on penis in males 4)Not predictable by history or protein C level 4)Not predictable by history or protein C level

COUMARIN Interactions POTENTIATORS:PhenylbutazoneCimetidineOmeprazoleAmiodarone Anabolic steroids ANTAGONISTS:BarbituratesRifampinPenicillinsAntacids

Warfarin n Pregnancy- NO

Contraindication towards administration of anticoagulants of indirect action n Hemorrhagic diatheses n Ulcer of stomach and duodenum n Ulcerative colitis n Pregnancy n Malignant formations n Disturbance of functions of kidneys, liver

Mechanism of action of thrombolytic agents n Blood plasma n Thrombus Profibrinolysin (plasminogen) Fibrinolysin (plasmin) Decomposition products Fibrinogen Profibrinolysin (plasminogen) Fibrin Fibrinolysin (plasmin) Fibrin Decomposition products Streptokinase+profibrinolysin Urokinase Activators Tissue activator of profibrinolysin

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

Administration of fibrinolytics Thrombosis, thromboembolia of: n - lungs n - brain n - eye retina Myocardium infarction Thromboses of profound veins Heparin often used after initial thrombolytic therapy

Side effects of fibrinolytics n Hemorrhages (prothrombine index (decreasing no less than %), clotting time (increasing no more than 2 times), fibrinogen content (not <1 h\l) should be under the constant control) n Allergic reactions (face hyperemia, abdominal pain, pain behind the sternum, chill, raised body temperature – these are reactions on foreign protein) n Contraindications: hemorrhagic diatheses, hemorrhages. Open wounds, ulcer disease. Nephritis, acute form of tbc, x-ray disease.

Drugs influencing on leuko- and erythropoesis

Combined drugs Actiferrin Iron sulfate, D,L- serin Iron sulfate, D,L- serin, glucose, fructose Caps., g syrup 5 ml – 171 mg 34,5 mg 34 mg Sorbifer-durules Iron sulfate, ascorbatic acid Tab., 320 mg 100 mg Ferrplect Iron sulfate, ascorbatic acid Tab., 50 mg 10 mg Ferroplex Iron sulfate, ascorbatic acid Tab., 50 mg 10 mg Fefol Iron sulfate, folic acid Tab., 150 mg 47 mg Ferro-folgamma Iron sulfate, folic acid, vit. В 12 Caps., 100 mg 20 mg Tardiferron-retard Iron sulfate, ascorbatic acid, mucoprotease Dragee, 256,3 mg 80 mg Gyno-tardiferron Iron sulfate, ascorbatic acid, mucoprotease, folic acid Dragee, 256, 3mg 80 mg Fenulse Iron sulfate, ascorbatic acid, nicotinamid, vitamins of B group Capsules 45 mg Irovit Iron sulfate, ascorbatic acid, folic acid, ciancobalamine, lysine Caps., 300 mg 100 mg Ferrostab Iron fumarate, folic acid Tab., 154 mg 33 % Folfetab Iron fumarate, folic acid Tab., 200,mg 33 % Globiron Iron fumarate, folic acid, vitt. В 6, В 12. Caps. Macrofer Iron gluconate, folic acid Tab., 625 mg 12 %

Iron SULFATE (gradumet substance)

Iron SULFATE+ascorbatic acid+mucoprotease

n

Iron SULFATE+ascorbatic acid

Multofer (Fe 3+ -hydroxide polymaltose complex)

Iron asparginate (Fe 3+ ) n

Iron fumarate

Criteria of iron drugs therapy effectiveness n Increasing of reticulocytes quantity on 5-7th day after administration n Normalization of blood iron-binding function indexes (not only indexes of peripheral blood) n If the latter get normalized during 1-2 months of therapy, than saturation of depot get normalized on 3rd month. On this stage dose of the drugs must be decreased to mg of elementary Fе per 2 hours. n If the reason of blood loss has been eliminated administration of the drugs is determined by iron metabolism indexes. n If the reason of iron loss is not eliminated supportive therapy is carried on according to the following: mg of elementary Fe per day during a week and after 3-4 weeks of brake and so on.

Complications of therapy with peroral iron drgus n Activation of free-radical processes n Nausea, vomiting, diarrhea (irritation of mucous membranes) n Constipations (FeS production) n Melena n Black coloring of teeth n Appearance of metallic taste in the mouth

Indications towards administration of parenteral forms of iron n Condition after gastrectomy n Condition after massive resection of small intestine n Heavy enteritis n Parenteral nutrition n Haemodyalysis n Psychogenic anorexia

Drugs for parenteral introduction Ferbitol Chelate substances Amp., 1 ml i.m. 50 mg Ferlecyt Chelate substances Sodium gluconate complex Amp., 1 ml i.m. Amp., 5 ml i.v. 50 mg 100 mg Fercoven Polynuclear hydroxyl complexes of iron, saccharate of iron, gluconate of cobalt Amp., 1 ml i.v. 20 mg Жектофер Polynuclear hydroxyl complexes of iron, sorbitol, citric acid Amp., 2 ml i.m. 100 mg Ferrum-lek Polynuclear hydroxyl complexes of iron. Polymaltose complex Amp., 2 ml i.m. Amp., 5 ml i.v. 100 mg Maltofer -\\- -\\- Amp., 2 ml i.m. 100 mg Venofer -\\- -\\- Amp., 5 ml i.v. 100 mg

Polynuclear hydroxyl complexes of iron (polyisomaltosate of iron)

Calculation of dose of drugs for parenteral introduction А=К х (100-6Hb) х 0,0066, where А – quantity of ampoules of drug with contents of 100 mg of Fe (per treatment coarse); К – patient’s body weight (kg); Hb – contents of hemoglobin in g % А=(К х 2,5) х [16,5-(1,3Hb)], where А – quantity of iron mg per coarse; К – body weight (kg); Hb – contents of hemoglobin (g\100 ml) More than 100 mg of elementary iron per day should not be introduced

Complications which develop during parenteral iron introduction n Phlebitis, after-injection abscesses, pain in the place of introduction; n Allergic reactions; n Hyperemia of face, neck, feeling of pressure behind sternum, pain in lumbal area, sternocardia (can be relieved with analgesics+0,5 ml of atropine sulfate); n Arterial hypotonia; n Darkening of skin in place of introduction. n Contraindications: hemochromatosis, liver diseases, coronary insufficiency, essential hypertension of ІІ – ІІІ stages, acute nephritis. n In case of acute poisoning with iron drugs deferroxamine and EDTA are introduced

Hyperchrome anemia n а) megaloblast n Erythroblast Hyperchrome megaloblast Megalocyte Cyanocobalamine, oxycobalamine (are transformed into cobamamid) and folic acid are introduced. б) macrocytar б) macrocytar Erythroblast Hyperchrome macronormoblast Macrocyte Erythroblast Hyperchrome macronormoblast Macrocyte Folic acid is used

Erythremia (polycytemia) n Anti-blastoma drug imifod and radioactive isotopes of phsophorus ( 32 Р) are used

Other drugs used for hypochrome anemia n Cobalt drus (coamid) n Human recombinant erythropoetin (eportin alfa, epogen, eprex)

Leucopoesis stimulants n Mechanism of action is based on their participation in piramidine bases synthesis, which are necessary for synthesis of nucleonic acids n Drugs: n - methyluracyl (doesn’t have irritative action, ways of introduction; perorally, rectally locally); n - pentoxyl (possesses irritative action, administered perorally after a meal, with milk); n - sodium nucleonate (introduced perorally and i.m., possesses irritative activity). n Nowadays also stimulants of new type were synthesized – activators of colony-producing factor of leucopoesis: n - molgramostim (granulocyte-macrophagal colony-stimulating factor and n - filgrastim (granulocytar colony-producing factori)

Folic acid n

n

Drugs which depress leucopoesis n Are administered in case of leucosis and lymphogranulomatosis n Antiblastome drugs refer to this group: n - methotrexate n - merkaptopurine n - chlorbutin n - mielosan n - vinblastin n - vinkristin