DRUGS USED IN COAGULATION DISORDERS

-drugs used to decrease clotting /to dissolve clots already present. - they interact at some point with the clotting process or cascade , a series of enzyme activation steps that originate within the blood it self ( intrinsic system) or in tissues ( extrinsic system).

Classification:
1)ANTICOAGULANTS 2)THROMBOLYTICS 3)ANTIPLATELET DRUGS

1)ANTICOAGULANTS

These are drugs to reduce the coagulability of blood . They may be classified into: A) Heparin , low molecular weight heparins and heparinoids (Heparan sulfate, Danaparoid, Lepirudin, Ancrod); B)Oral anticoagulants: b1) Coumarin derivatives-Dicoumarol, Warfarin sod., Acenocoumarol, Etylbiscoumacetate; b2) Indandione derivative: Phenindione.

A)1. *HEPARIN
It is a large sulfated polysaccharide present in all tissues containing mast cells: lung, liver and intestinal mucosa. It is commercially produced from ox lung and pig intestinal mucosa. It has a molecular weight of about 15.000 ( 10.000 to 20.000).

Actions:
a) anticoagulant It acts indirectly by activating plasma antithrombin III (AT III, a serine proteinase inhibitor) and probably other similar cofactors. The heparin AT III complex then binds to clotting factors of the intrinsic and common pathways ( Xa, IIa, IXa,XIa, XIIa and XIIIa) and inactivates them. The anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin (IIa) mediated conversion of fibrinogen to fibrin. Higher doses of Heparin given for some time cause reduction in AT-III levels , probably a compensatory phenomenon.

b)platelet aggregation ; c)lipemia clearing-injection of heparin clears turbid post-prandial lipemic plasma. Heparin releases a lipoprotein lipase from the vessels wall and tissues which hydrolyses triglycerides of chylomicra and very low density lipoproteins to free fatty acids; these than pass into tissues and the plasma looks clear.

Pharmacokinetics:
Heparin is a large , highly ionized molecule ; therefore it is not absorbed orally. Injected i.v. it acts spontaneously and after s.c. injection anticoagulant effect develops after ~ 60 minutes.Bioavailability of s.c. heparin is inconsistent. It is not administered i.m. because of risk of hematoma. Heparin does not cross blood-brain barrier or placenta ( it is the anticoagulant of choice during pregnancy).It is metabolized in the liver and fragments are excreted in urine. Heparin released from mast cells is degraded by tissue macrophages it is not a physiologically circulating anticoagulant.

The units of measure are units. 1U is the amount of heparin that will prevent 1 ml of plasma from clotting after the addition of 0,2% ml of 1% CaCl2 solution. Heparin sod. 1 mg has 120-140 U of activity.

Adverse effects:
-bleeding ; -thrombocytopenia ( mild and transient and occurs due to aggregation of platelets); -transient and reversible alopecia is infrequent; -osteoporosis may develop on long term use of relatively high doses; -hypersensitivity reactions-they are rare : urticaria, fever.

Doses:
Usual dose: * i.v. in bolus: 5000-10.000 U, every 4-6 hours. The dose and frequency is controlled by APPT((aPTT=activated partial thromboplastin time) measurement which is kept at 50-80 seconds or 1.5-2.5 times the patients pretreatment value.

2.*LOW MOLECULAR WEIGHT(LMW) HEPARINS

Heparin has been fractionated into LMW forms ( with molecular weights 3000-7000 ) by different techniques. They selectively inhibit factor Xa with little effect on IIa. They act only by inducing a conformational change in AT III and not by bringing together AT III and thrombin. Also they appear to have lesser antiplatelet action . Thrombocytopenia is less frequent.

The more important advantages of LMW heparins and pharmacokinetic: -better subcutaneous availability( 70-90% ) compared to unfractionated heparin ( 20-30 %); -once daily s.c. administration ( not every 4-6 hours like heparin); -laboratory monitoring is not needed ( since APTT clotting times are not prolonged); dose is calculated on body weight basis; Most studies have found LMW heparins to be equally efficacious to unfractionated heparin.

Indications of LMW heparins are: -prophylaxis of deep vein thrombosis and pulmonary embolism in high risk patients undergoing surgery , stroke or other immobilized patients; -treatment of established deep vein thrombosis -unstable angina.

The most important are : ENOXAPARIN, REVIPARIN, NADROPARIN, DALTEPARIN, PAMPARIN, ARDEPARIN. They are administered s.c.

3. *HEPARINOIDS
HEPARAN SULFATE-it is a heparin-like natural substance found in many tissues.It is less potent anticoagulant than heparin . It is believed to be a physiological antithrombotic at the surface of vascular endothelium. DANAPAROID-it is a preparation containing mainly heparin sulfate obtained from pig gut mucosa, which is used in cases with heparin induced thrombocytopenia. LEPIRUDIN-it is a recombinant preparation of hirudin ( a polypeptide anticoagulant secreted by salivary glands of leech) ; it acts by inhibiting thrombin directly. It is indicated in patients with heparin induced thrombocytopenia.

4. *HEPARINE ANTAGONIST
PROTAMINE SULFATE -it is a strongly basic, low molecular weight protein obtained from the sperm of certain fish. -given i.v. it neutralises heparin. -in the absence of heparine , it itself acts as a weak anticoagulant by interacting with platelets and fibrinogen.

B) *ORAL ANTICOAGULANTS
b)ORAL ANTICOAGULANTS WARFARIN and its congeners act as anticoagulants only in vivo, not in vitro. They act indirectly by interfering with the synthesis of vit K dependent clotting factors in liver ( VII, IX, X). The anticoagulant effect develops gradually ( 1-3 days ) as the levels of the clotting already in plasma decline progressively. The differences between different oral anticoagulants are primarily pharmacokinetic and in the adverse side effects produced by them.

The most important oral anticoagulants are: *Racemic Warfarin sod. it is the most popular oral anticoagulant. *Dicoumarol-it is slowly and unpredictably absorbed orally. *Acenocoumarol-acts more rapidly.

Adverse effects:
-bleeding: ecchymosis, epistaxis, hematuria, bleeding in the gastrointestinal tract etc. Treatment of bleedings: *withhold the anticoagulant; *give fresh blood transfusion; *give vit K1-specific antidote. -warfarin causes: alopecia, dermatitis, diarrhoea; -acenocoumarol causes: oral ulceration, gastrointestinal disturbances, dermatitis, alopecia, urticaria etc. -dicoumarol may cause: frequent gastrointestinal disturbances.

Clinical uses of anticoagulants:

-treatment and prevention of deep vein thrombosis and pulmonary embolism; in elederly , postoperative, postpartum , poststroke and leg fracture patients and also for patients undergoing elective surgery; -myocardial infarction: They may benefit by preventing mural thrombi at the site of infarction and venous thrombi in leg veins. For secondary prophylaxis against a subsequent attack anticoagulants are inferior to antiplatelet drugs. Heparin (i.v.) for 2-8 days followed by oral anticoagulants for 3 months or low dose s.c. heparin are generally given after recanalization of coronary artery by fibrinolytic therapy.

-unstable angina-aspirin+heparin followed by warfarin. -rheumatic heart disease , atrial fibrillation warfarin / low dose of aspirin are effective in preventing embolism from fibrillating atria; -cerebrovascular disease-They may be used in cerebral embolism , because showers of emboli are often recurrent and can be prevented by anticoagulants. -vascular surgery , prosthetic heart valves, retinal vessels thrombosis , extracorporeal circulation, haemodialysisanticoagulants are indicated along with antiplatelet drugs for prevention of thromboembolism. -disseminated intravascular coagulation The coagulation factors get consumed for the formation of intravascular microclots and blood is incoagulable.Heparin paradoxically checks bleedings in such patients by preserving the clotting factors.However, in some cases heparin may aggravate bleeding.

2)THROMBOLYTICS ( FIBRINOLYTICS)

These are drugs used to lyse thrombi / clot to recanalyse occluded blood vessels ( mainly coronary artery).They are curative rather than prophylactic. Mechanism of action: They work by activating the natural fibrinolytic system. All act either directly or indirectly to convert plasminogen to plasmin( the normal endogenous fibrinolytic enzyme which splits fibrin into fragments , promoting the breakdown and dissolution of the clot). The most important fibrinolytics are: STREPTOKINASE, UROKINASE, ALTEPLASE.

STREPTOKINASE: It is obtained from beta-haemolytic Streptococci group C. It is inactive as such: it combines with plasminogen activator complex which then causes limited proteolysis of other plasminogen molecules to plasmin. It is administered by i.v. infusion. Streptokinase is antigenic : can cause hypersensitivity reactions and anaphylaxis, specially when used second time in a patient; fever is common, hypotension and arrhythmias are reported. However , it is the least expensive of the 3 fibrinolytics.

UROKINASE: It is an enzyme isolated from human urine; now prepared from cultured human kidney cells.It activates plasminogen directly . It is nonantigenic .Fever occurs during treatment , but allergic phenomenas are rare. It is administered i.v. ALTEPLASE( RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR - r t-PA- ) Produced by recombinant DNA technology from human tissue culture , it specifically activates gel phase plasminogen already bound to fibrin and has little action on circulating plasminogen. It is administered i.v.

Clinical uses of fibrinolytics:

-acute myocardial infarction: it is the chief indication ; now considered a first line approach if fibrinolytic therapy can be instituted within 12 hours of symptom onset. Recanalization of thrombosed coronary artery has been achieved in 50-90 % cases.Fibrinolytic therapy has also been used in unstable angina ; -deep vein thrombosis in leg, pelvis, with reduced risk of pulmonary embolism ; -pulmonary embolism; -peripheral arterial occlusion-fibrinolytics recanalise ~ 40% limb artery occlusions , specially those treated within 72 hours. Peripheral arterial thrombolysis is followed by short-term heparin and long term aspirin therapy.Fibrinolytics have no role in chronic peripheral vascular diseases.

ANTIFIBRINOLYTICS
These are drugs which inhibit plasminogen activation and dissolution of clot. EPSILON AMINO-CAPROIC ACID (EACA), TRANEXAMIC ACID, APROTININ: Clinicaluses: they are administered by i.v. infusion in: -overdose of streptokinase/ urokinase/alteplase; -certain traumatic and surgical bleedings; - after cardio-pulmonary bypass surgery; - after prostatic surgery , tooth extraction

3. ANTIPLATELET DRUGS

They interfere with platelet function and may be useful in the prophylaxis of thromboembolic disorders. -Antiplatelet drugs are more useful in arterial thrombosis while anticoagulants are more effective in venous thrombosis. Drugs interfering with platelet function are: *ASPIRIN: -it inhibits COX and TX-synthetase-inactivating them irreversiblythe result is inhibition of TxA2 synthesis.Aspirin also inhibits PGI2 synthesis in vessels wall.!!However, since intimal cells can synthesize fresh enzyme , activity returns rapidly. -It is possible that at low doses ( 75-150 mg /day or 300 mg twice weekly) TxA2 formation by platelets is selectively suppressed whereas higher doses( > 900 mg/day) may decrease both TxA2 and PGI2 production.

*DIPYRIDAMOLE -it is a vasodilator which was introduced for angina pectoris; -it inhibits phosphodiesterase and blocks uptake of adenosine to increase platelet cAMP which potentiates PGI2 and interferes with aggregation. -Dipyridamole alone has little clinically significant effect but improves the response to warfarin , along with which is used to decrease the incidence of thromboembolism in patients with prosthetic heart valves. It is administered orally, 150-300 mg/day.

*TICLOPIDINE It is a thienopyridine which alters surface receptors on platelets and inhibits ADP as well as fibrinogen induced platelet aggregation. It is well absorbed orally ; peak antiplatelet effect is produced after 8-10 days therapy. *CLOPIDOGREL -it is the newer congener of ticlopidine better tolerated. -it is administered orally. *GLYCOPROTEIN (GP) IIb/IIIa antagonists: -they act by blocking GP IIb/IIIa receptor for fibrinogen and for van Willebrand factor through which agonists like collagen, thrombin, TxA2 , ADP etc. induce platelet aggregation.

*ABCIXIMAB -it is the Fab fragment of an antibody against GP IIb/IIIa ; -given along with aspirin and heparin during coronary angioplasty it has markedly reduced the incidence of restenosis, subsequent myocardial infarction and death. It is administered i.v.; it is very expensive.

Clinical uses of antiplatelet drugs:

-coronary artery disease: *myocardial infarction, ( low dose of aspirin started immediately after myocardial infarction has been found to reduce mortality and prevent reinfarction; also prevents reocclusion after thrombolytic therapy), *unstable angina, *primary and secondary prevention of myocardial infarction ( aspirin 75-150 mg/day given to all individuals with evidence of coronary artery disease and in those with risk factors for the same).

-cerebrovascular disease( aspirin may reduce the incidence of

transient cerebral attacks in patients with persistent atrial fibrillation, or in those with history of stroke).

-coronary bypass implants-incidence of reocclusion is reduced by aspirin/ticlopidine/clopidrogel). -prosthetic

heart valves ; -peripheral vascular disease-reduce the incidence of

thromboembolism.

DRUGS USED IN ANAEMIAS

These are agents required in the formation of blood and are used for treatment of anaemias. Anaemias occur when the balance between production and destruction of red blood cells is disturbed by: *Blood loss ( acute or chronic); *Impaired red cell formation due to deficiency of essential factors i.e. iron, vitamin B 12 , folic acid ; bone marrow depression ( hypoplastic anaemias ), erythropoietin deficiency.

IRON
Iron has for long been considered important for the body. Distribution of iron in the body: total body iron in an adult is 2,5-5 g ( average 3,5 g); it is more in men ( 50 mg/kg) than in women ( 38 mg/kg) .It is distributed into : haemoglobin ( 66%), iron stores as ferritin and haemosiderin ( 25%), myoglobin ( in muscles), parenchymal iron ( as constituent of enzymes) . Daily requirement: adult male: 0,5-1 mg; adult female: 1-2 mg; children: 25 g /kg. Dietary sources of iron: rich: liver, egg yolk, dry beans, dry fruits; medium: meat, chicken, fish, spinach, banana,apple; poor: milk and its products.

Preparations and dosages:

ORAL:some simple oral preparations are: ferrous sulfate, ferrous gluconate, ferrous fumarate, colloidal ferrichydroxide.Dissociable ferrous salts are inexpensive , have high iron content and are better absorbed than ferric salts specially at higher doses.Gastric irritation and constipation ( the most important side effects of oral iron ) are related to the total quantity of elemental iron administered. Other forms : iron present in ferrous succinate, iron choline citrate, iron calcium complex , ferric ammonium citrate (oral formulations ) etc. These are claimed to be better absorbed and / or produce less bowel upset, but this is primarily due to lower iron content.They are generally more expensive.

 A total of 200 mg of elemental iron ( in infants and children 3-5 mg/kg) given daily in 3 divided doses produces the maximal haemopoietic response. Adverse effects of oral iron: constipation, epigastric pain, heart burn, nausea, vomiting etc.

PARENTERAL: iron-dextrane, iron-sorbitol citric acid complex.They are administered deep i.m. , i.v. Iron therapy by injection is indicated only when: -oral iron is not tolerated( bowel upset is too much); -failure to absorb oral iron : malabsorbtion, inflammatory bowel disease, chronic inflammation ( rheumathoid arthritis) etc. -non-compliance to oral iron; -in presence of severe deficiency with chronic bleeding. Parenteral iron therapy needs calculation of the total iron requirement of the patient ( according to the body weight). Adverse effects of parenteral therapy: pain at the site of i.m. injection, sterile abscess, fever, headache, joint pains, chest pain, metallic taste in the mouth, rare anaphylactic reaction.

Clinical uses of iron preparations:

-iron deficiency anaemia caused by: *nutritional deficiency, * chronic bleeding from gastrointestinal tract, *repeated attacks of malaria, *chronic inflammatory diseases. Iron should be normally administered orally ; parenteral therapy is reserved to special circumstancies. A rise of Hb level by 0,5-1 g/dl per week is an optimum response to iron therapy.It is faster in the beginning and when anaemia is severe. Later, the rate of increase in Hb% declines. However, therapy should be continued till normal Hb level is attained ( generally takes 1-3 months depending on the severity) and 2-4 months thereafter to replenish stores because after correction of anaemia iron absorbtion is slow.

Iron balance is disturbed also in menstruation, later half of pregnancy , infancy in these situations prophylactic use of iron is indicated.

-megaloblastic anaemia; -as an astringent-ferric chloride is used in throat pain.

VITAMIN B12 AND FOLIC ACID

Deficiecy of vitamin B12 and folic acid which are B group vitamins results in megaloblastic anaemia characterized by the presence of large red cells precursors in bone marrow and their large and shortlived progeny in peripheral blood.The basic defect is in DNA synthesis. Vitamin B12 and folic are called maturation factors.

VITAMIN B12
-cyancobalamin and hydroxocobalamin are complex cobalt containing compounds present in diet and referred as vit. B12. -vitamin B12 occurs as water soluble , thermostable red crystals.It is synthesized in nature only by microorganisms ; plants and animals acquire it from them. Dietary sources:liver, kidney, sea fish, egg yolk, meat, cheese, legumes. Vitamin B12 is synthetised by the colonic microflora but this is not available for absorbtion in man. The commercial source is Streptomyces griseus. Daily requirement: 1-3 g, pregnancy and lactation 3-5 g.

Deficiency of Vitamin B12 occurs due to: -addisonian pernicious anaemia: is probably an autoimmune disorder which results in destruction of gastric parietal cells absence of intrinsic factor in gastric juice ( along with achlohydria) inability to absorb vit. B12. -other causes of gastric mucosal damage ( chronic gastritis, gastric carcinoma, gastrectomy etc.); -malabsorbtion ( damaged intestinal mucosa), bowel resection; -consumption of B12 by abnormal flora in intestine ; -nutritional deficiency; -increased demand ( pregnancy, infancy).

Manifestations of deficiency: -megaloblastic anaemia; -glossitis; -neurological: degeneration of spinal cord, peripheral neuritis, poor memory, mood changes etc.

Preparations, dose , administration: CYANCOBALAMIN, HYDROXOCOBALAMIN, METHYLCOBALAMIN They are administered parenterally ( i.m. / deep s.c.)/ orally. Parenteral administration is necessary when B12 deficiency is due to lack of intrinsic factor. Initially 30100 g / day for 10 days followed by 100 g weekly and then monthly for maintenance ( for life long). When neurological complications are present higher doses are used ( 500-1000 g /day). In other types of deficiency 10-30 g / day may be used orally.The prophylactic dose is 3-10 g / day. They may be used in combinations with other vitamins and iron.

 Clinical uses: -treatment of vit. B12 deficiency: B12 is used as outlined before. It is used in combination with iron and with folic acid.Response to B12 is rapid symptomatic improvement starts in 2 days , mucosal lesions heal in 1-2 weeks.Neurological parameters improve more slowly-may be several months; full recovery may not occur if vit. B12 deficiency has been sever or had persisted for long. -mega doses of Vit. B12 have been used in neuropathies , psychiatric disorders and as a general tonic to allay fatigue, improve growth. Side effects:allergic reactions have occurred in injections; anaphylactoid reactions have occurred on i.v. injection ( this route should not be used).

FOLIC ACID
It occurs as yellow crystals which are insoluble in water but its sodium salt is freely water soluble. Dietary sources: liver, green leafy vegetables ( spinach), egg, meat, milk.It is synthetised by gut flora, but this is largely unavailable for absorbtion. Daily requirement of an adult: < 0.1 mg but dietary allowance of 0.2 mg / day is recommended. During pregnancy , lactation or any condition of high metabolic activity, 0.8 mg/day is considered appropriate.

Deficiency:folate deficiency occurs due to: Inadequate dietary intake; Malabsorbtion: especially involving upper intestine; Chronic alcoholism; Increased demand: pregnancy, lactation, rapid growth periods, haemolyitic anaemia. Drug induced: prolonged therapy with anticonvulsants ( phenytoin, phenobarbitone), oral contraceptives-interfere with absorbtion of folate.

Manifestations of deficiency: Megaloblastic anemia, indistinguishable from that due to B12 deficiency.However, folate deficiency develops more rapidly if external supply is cut off: body stores last 3-4 months only. Epithelial damage: glossitis, enteritis, diarrhoea. General debility, weight loss, sterility. Preparations , dosages: FOLIC ACID liquid oral preparations , injectables are available only in combination formulations ( with B12, other vitamins) . Oral therapy is adequate except when malabsorbtion is present or in severely ill patient-given i.m. Dose: therapeutic 2 to 5 mg /day , prophylactic 0,5 mg/day.

Clinical uses: -megaloblastic anaemias due to: nutritional folate deficiency, increased demand ( pregnancy, lactation, infancy, ), pernicious anaemia ( folate stores may be low- adjuvant role), malabsorbtion syndromes, antiepileptic therapy . -prophylaxis of folate deficiency: only when predisposing factors are present. -methotrexate toxicity: folinic acid ( leucovorin) antagonizes the toxicity of methotrexate. Side effects:oral folic acid is entirely nontoxic; injections rarely cause sensitivity reactions.