Drugs affecting Drugs affecting haemostasis, haemostasis,

Antianemic drugsAntianemic drugs A. KohútA. Kohút

Drugs used to treat blood Drugs used to treat blood disordersdisorders

1. Anticoagulants1. Anticoagulants 2. Antiagregatory drugs 2. Antiagregatory drugs

(antiplatelets)(antiplatelets) 3. Thrombolytics3. Thrombolytics 4. Antifibrinolitics4. Antifibrinolitics 5. Drugs for anemia5. Drugs for anemia

AnticoagulantsAnticoagulants

Hemostasis:Hemostasis: Injury

PlateletActivation

Plt-Fusion

Blood Vessel Constriction

CoagulationActivation

Stable Hemostatic Plug

Thromibn,

Fibrin

Reduced

Blood flow

Tissue Factor

Primary hemostatic plug

Neural

Coagulation:Coagulation:Intrinsic 12,11,9,8

(aPTT-)Extrinsic-7

(PT)

Prothrombin Thrombin

Fibrinogen Fibrin

Common Path (TT)FX FXa

Process- Process- primary primary haemostasishaemostasis In a normal individual, In a normal individual,

coagulation is initiated within 20 coagulation is initiated within 20 seconds after an injury occurs to seconds after an injury occurs to the blood vessel damaging the the blood vessel damaging the endothelial cellsendothelial cells. .

PlateletsPlatelets immediately form a immediately form a haemostatic plug at the site of haemostatic plug at the site of injury. This is called injury. This is called primary primary haemostasishaemostasis. .

Secondary haemostasisSecondary haemostasis

Secondary haemostasis then follows—Secondary haemostasis then follows—plasmaplasma components called components called coagulation factorscoagulation factors respond (in a complex cascade) to form respond (in a complex cascade) to form fibrinfibrin strands which strengthen the platelet plug. strands which strengthen the platelet plug.

Contrary to popular belief, coagulation from Contrary to popular belief, coagulation from a cut on the skin is not initiated by air or a cut on the skin is not initiated by air or drying out, but by platelets adhering to and drying out, but by platelets adhering to and activated by activated by collagencollagen in the blood vessel in the blood vessel endotheliumendothelium. .

The activated platelets then release the The activated platelets then release the contents of their granules, these contain a contents of their granules, these contain a variety of substances that stimulate further variety of substances that stimulate further platelet activation and enhance the platelet activation and enhance the haemostatic process.haemostatic process.

Mechanism of action of warfarinMechanism of action of warfarin

Comparisson of heparin and Comparisson of heparin and warfarinwarfarin

Unfractionated heparin UFH)

• (UFH) is able to inactivate fa IIa through formation of a tertiary complex, unlike LMWH.

• UFH binds more to plasma proteins, endothelium and macrophages, resulting in reduced bioavailability and greater patient variability to a given dose.

• UFH inactivates factors IIa and Xa and affects the aPTT, a measure of anti-factor IIa activity. (aPTT=activated partial thromboplastin time)

Low molecular weight size heparin (LMW)

• LMW heparins are fragments of parent heparins (1/3 of parent compound.

• Inhibit fa Xa and augment tissue-factor-pathway inhibitor

• minimally affect thrombin, or factor IIa

• Thus, a measure of antithrombin (anti-factor IIa) activity (aPTT=activated partial thromboplastin time) , is not used to measure the activity of LMW heparins,

• requires instead a specific anti-Xa assay.

Indication and Indication and contraindication of contraindication of

anticoagulants anticoagulants IndicationsIndicationsAtrial fibrilation,Atrial fibrilation,

Venouse Venouse thromboembolism,thromboembolism,

Acute myocardial Acute myocardial infarction,infarction,

Prevention of venous Prevention of venous thromboembolismthromboembolism..

ContraindicationsContraindicationsSevere hypertension,Severe hypertension,

Recent cerebral Recent cerebral haemorhage,haemorhage,

Gastric ulcer,Gastric ulcer,

Severe liver and renal Severe liver and renal disease,disease,

Pregnancy (warfarin),Pregnancy (warfarin),

Preexisting bleeding Preexisting bleeding disorders.disorders.

Heparin induced Heparin induced thrombocytopeniathrombocytopenia

Heparin-Antibiotic Heparin-Antibiotic InteractionsInteractions

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

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

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

- Clinical bleeding has been less frequently reported with - Clinical bleeding has been less frequently reported with Cefotetan than with cefoperazone or cefamandole.Cefotetan than with cefoperazone or cefamandole.

Drugs and conditions interacting Drugs and conditions interacting

with with warfarinwarfarin

The action of thrombolitics The action of thrombolitics and antifibrinolytics and antifibrinolytics

The action of thrombolitics and antifibrinolytics

Therapeutic usesTherapeutic usesof thrombolitics and of thrombolitics and

antitfibrinolyticsantitfibrinolytics

Thrombolitics :Thrombolitics : treatment of treatment of myocardial infarction, acute myocardial infarction, acute thrombotic strokethrombotic stroke

Antifibrinolytics:Antifibrinolytics: excessive bleeding excessive bleeding

after dental extraction in after dental extraction in haemophiliacshaemophiliacs

after overdoses of streptokinaseafter overdoses of streptokinase

DRUG USED TO TREAT BLEEDINGDRUG USED TO TREAT BLEEDING

Vitamin KVitamin K formation of clotting formation of clotting

factors II, VII, IX and Xfactors II, VII, IX and X given orally, i.m. or i.v. given orally, i.m. or i.v. synthetic preparation synthetic preparation

((menadiolmenadiol sodium sodium diphophatediphophate) ) is is water water soluble and thus not soluble and thus not require bile salt for its require bile salt for its absorptionabsorption

Clinical use:Clinical use: - bleeding - bleeding caused by the oral caused by the oral anticoagulants, - anticoagulants, - hypoprotrombinemia in hypoprotrombinemia in newborn (intestinal flora newborn (intestinal flora is not is not established)established)

Aprotinin - Aprotinin - antifibrinoliticantifibrinolitic

Aminocaproic acid, Aminocaproic acid, tranexamic acid, tranexamic acid, -- bleeding after bleeding after fibrinolytic therapy.- fibrinolytic therapy.- inhibit plasminogen inhibit plasminogen activationactivation

Protamine sulfateProtamine sulfate - antagonizes the - antagonizes the

anticoagulant effect of anticoagulant effect of heparinheparin

- positively charged - positively charged protein interacts with protein interacts with negatively negatively charged charged heparin to form stable heparin to form stable complex without complex without anticoagulant activityanticoagulant activity

Antiagregatory drugsAntiagregatory drugs(Antiplatelet drugs)(Antiplatelet drugs)

Mechanisms of action of Mechanisms of action of

antiplatelet drugsantiplatelet drugs

Antianemic drugsAntianemic drugs

Causes of anaemiaCauses of anaemia Inadequate productionInadequate production of red blood cells in of red blood cells in

bone marrow due to:bone marrow due to: Lack of raw materials e.g. nutritional anaemia. Lack of raw materials e.g. nutritional anaemia. Depression of bone marrow e.g. chronic infections, Depression of bone marrow e.g. chronic infections,

drugs, radiation etc. drugs, radiation etc. Infiltration of bone marrow in conditions like Infiltration of bone marrow in conditions like

malignancy.malignancy. Excessive destructionExcessive destruction of red blood cells due to: of red blood cells due to:

Abnormality of haemoglobin like thalassemia, Abnormality of haemoglobin like thalassemia, Deficiency of red cell enzymesDeficiency of red cell enzymes like Glucose 6 like Glucose 6

phosphate dehydrogenase deficiency, phosphate dehydrogenase deficiency, Abnormality of red cell membrane like hereditary Abnormality of red cell membrane like hereditary

sperocytosis sperocytosis Auto immune haemolytic anaemiasAuto immune haemolytic anaemias

Blood lossBlood loss due to any cause due to any cause

Megaloblastic anaemiaMegaloblastic anaemia Deficiency of vitamin B12 or folate or bothDeficiency of vitamin B12 or folate or both..

Deficiency of these nutrients may be due to: Deficiency of these nutrients may be due to: Decreased intake -Decreased intake - vitamin B12 deficiency is vitamin B12 deficiency is

seen in strict vegetarians. Over cooking in seen in strict vegetarians. Over cooking in boiling water reduce folate content in food. boiling water reduce folate content in food.

Impaired absorptionImpaired absorption - due to disease of - due to disease of gastrointestinal tract and surgical resection gastrointestinal tract and surgical resection of intestine. of intestine.

Defective utilisationDefective utilisation - due to drugs like few - due to drugs like few types of cancer drugs and epilepsy drug types of cancer drugs and epilepsy drug interfere with metabolism of folic acids. interfere with metabolism of folic acids.

Increased demandIncreased demand - pregnancy, recovery - pregnancy, recovery from chronic illness etc. from chronic illness etc.

Microcytic anaemiaMicrocytic anaemia

Due to reduced intakeDue to reduced intake or absorption of or absorption of ironiron: : Iron poor diet Iron poor diet Malabsorption syndromes Malabsorption syndromes Chronic diarrhoea Chronic diarrhoea Gastrointestinal surgery Gastrointestinal surgery

Due to increased loss:Due to increased loss: Gastrointestinal bleeding due to any cause Gastrointestinal bleeding due to any cause Hook worm infestation Hook worm infestation Bleeding disorders Bleeding disorders Excessive menstruation Excessive menstruation

Due to increased demands:Due to increased demands: Pregnancy Pregnancy Lactation Lactation Prematurity and low birth weight Prematurity and low birth weight Adolescence Adolescence Chronic illness Chronic illness

Types and the treatment of Types and the treatment of anaemiasanaemias

Hematopoietic growth factors

• SCF - stem cell factor • BFU-E - . burst-forming units

erythroblasts • CFU-E- colony-forming units

erythroid • GM-CSF, granulocyte-

macrophage colony-stimulating factor interleukin-4, and interleukin-9.

• EPO - erythropoietin is a specific distal acting factor, which stimulates maturation of CFU-E to mature erythrocytes.

Factors involved in the development of anaemia and the role of EPO

• TNF may inhibit the actions of erythropoietin,

• IL-1 affect utilization EPO

• IF-beta and IF-gamma suppress erythropoiesis.

• administration of

• EPO can actually improve anemia across a wide range of disease states.