l3 Anticoagulants, Diuretics , Antidiuretics

7/30/2019 l3 Anticoagulants, Diuretics , Antidiuretics

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DRUGS USED IN COAGULATION

DISORDERS

-drugs used to decrease clotting /todissolve clots already present.

- they interact at some point with the

clotting process or cascade , a series ofenzyme activation steps that originate

within the blood it self ( intrinsic system) orin tissues ( extrinsic system).


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Classification:

1)ANTICOAGULANTS

2)THROMBOLYTICS

3)ANTIPLATELET DRUGS


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1)ANTICOAGULANTS


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These are drugs to reduce the coagulability ofblood .

They may be classified into:

A) Heparin , low molecular weight heparins andheparinoids (Heparan sulfate, Danaparoid,

Lepirudin, Ancrod);

B)Oral anticoagulants:

b1) Coumarin derivatives-Dicoumarol, Warfarinsod., Acenocoumarol, Etylbiscoumacetate;

b2) Indandione derivative: Phenindione.


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A)1. *HEPARIN

It is a large sulfatedpolysaccharide 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 ofabout 15.000 ( 10.000 to 20.000).


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Actions:

a) anticoagulant

It acts indirectly by activating plasma antithrombinIII (AT III, a serine proteinase inhibitor) and probablyother similar cofactors.

The heparinAT 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 byinhibition of factor Xa as well as thrombin (IIa) mediatedconversion of fibrinogen to fibrin.

Higher doses of Heparin given for some time causereduction in AT-III levels , probably a compensatoryphenomenon.


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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 thanpass into tissues and the plasma looks clear.


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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 ~ 60minutes.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 orplacenta ( it is the anticoagulant of choice duringpregnancy).It is metabolized in the liver and fragmentsare excreted in urine.

Heparin released from mast cells is degraded bytissue macrophagesit is not a physiologicallycirculating anticoagulant.


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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.


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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.


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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.


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2.*LOW MOLECULAR WEIGHT(LMW)

HEPARINS

Heparin has been fractionated into LMWforms ( with molecular weights 3000-7000 ) bydifferent techniques.

They selectively inhibit factor Xa with littleeffect on IIa.

They act only by inducing a conformationalchange in AT III and not by bringing together AT IIIand thrombin.

Also they appear to have lesser antiplateletaction .

Thrombocytopenia is less frequent.


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The more important advantages of LMW heparinsand pharmacokinetic:

-better subcutaneous availability( 70-90% )compared to unfractionated heparin ( 20-30 %);

-once daily s.c. administration ( not every 4-6 hourslike heparin);

-laboratory monitoring is not needed ( since APTTclotting times are not prolonged); dose iscalculated on body weight basis;

Most studies have found LMW heparins to beequally efficacious to unfractionated heparin.


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Indications of LMW heparins are:

-prophylaxis of deep vein thrombosis andpulmonary embolism in high risk patients

undergoing surgery , stroke or otherimmobilized patients;

-treatment of established deep vein

thrombosis-unstable angina.


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The most important are : ENOXAPARIN,

REVIPARIN, NADROPARIN, DALTEPARIN,

PAMPARIN, ARDEPARIN.

They are administered s.c.


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3. *HEPARINOIDS

HEPARAN SULFATE-it is a heparin-like natural substancefound in many tissues.It is less potent anticoagulantthan heparin . It is believed to be a physiologicalantithrombotic at the surface of vascular endothelium.

DANAPAROID-it is a preparation containing mainlyheparin sulfate obtained from pig gut mucosa, which isused in cases with heparin induced thrombocytopenia.

LEPIRUDIN-it is a recombinant preparation of hirudin ( apolypeptide anticoagulant secreted by salivary glands

of leech) ; it acts by inhibiting thrombin directly.It is indicated in patients with heparin induced

thrombocytopenia.


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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.


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B) *ORAL ANTICOAGULANTS

b)ORAL ANTICOAGULANTS

WARFARIN and its congeners act as anticoagulants onlyin vivo, not in vitro.

They actindirectly by interfering with the synthesis of vitK dependent clotting factors in liver ( VII, IX, X).

The anticoagulant effect develops gradually ( 1-3 days ) asthe levels of the clotting already in plasma decline

progressively.The differences between different oral anticoagulants are

primarily pharmacokinetic and in the adverse sideeffects produced by them.


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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.


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Adverse effects:

-bleeding: ecchymosis, epistaxis, hematuria, bleeding in thegastrointestinal 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, gastrointestinaldisturbances, dermatitis, alopecia, urticaria etc.

-dicoumarol may cause: frequent gastrointestinaldisturbances.


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Clinical uses of anticoagulants:

-treatment and prevention of deep vein thrombosis andpulmonary embolism; in elederly , postoperative,postpartum , poststroke and leg fracture patients and alsofor patients undergoing elective surgery;

-myocardial infarction:

They may benefit by preventing mural thrombi at the site ofinfarction and venous thrombi in leg veins.

For secondary prophylaxis against a subsequent attackanticoagulants are inferior to antiplatelet drugs.

Heparin (i.v.) for 2-8 days followed by oral anticoagulants for 3months or low dose s.c. heparin are generally given afterrecanalization of coronary artery by fibrinolytic therapy.

unstable angina aspirin+heparin followed by warfarin


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-unstable angina-aspirin+heparin followed by warfarin.

-rheumatic heart disease , atrial fibrillationwarfarin / 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, haemodialysis-

anticoagulants are indicated along with antiplatelet drugs for

prevention of thromboembolism.

-disseminated intravascular coagulationThe coagulation

factors get consumed for the formation of intravascularmicroclots and blood is incoagulable.Heparin paradoxically

checks bleedings in such patients by preserving the clotting

factors.However, in some cases heparin may aggravate

bleeding.


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2)THROMBOLYTICS

( FIBRINOLYTICS)


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These are drugs used to lyse thrombi / clot to

recanalyse occluded blood vessels ( mainlycoronary artery).They are curative rather than

prophylactic.Mechanism of action:

They work by activating the naturalfibrinolytic system.

All act either directly or indirectly to convertplasminogen to plasmin( the normal endogenousfibrinolytic enzyme which splits fibrin intofragments , promoting the breakdown and

dissolution of the clot).The most important fibrinolytics are:

STREPTOKINASE, UROKINASE, ALTEPLASE.


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STREPTOKINASE:

It is obtained from beta-haemolytic

Streptococci group C.It is inactive as such: it combines with

plasminogen activator complex which thencauses limited proteolysis of other plasminogen

molecules to plasmin.It is administered by i.v. infusion.

Streptokinase is antigenic : can causehypersensitivity reactions and anaphylaxis,

specially when used second time in a patient;fever is common, hypotension and arrhythmiasare reported. However , it is the least expensiveof the 3 fibrinolytics.


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UROKINASE:

It is an enzyme isolated from human urine;now prepared from cultured human kidney

cells.It activates plasminogen directly . It isnonantigenic .Fever occurs during treatment , butallergic phenomenas are rare. It is administeredi.v.

ALTEPLASE( RECOMBINANT TISSUE PLASMINOGENACTIVATOR - r t-PA- )

Produced by recombinant DNA technology fromhuman tissue culture , it specifically activates gel

phase plasminogen already bound to fibrin andhas little action on circulating plasminogen. It isadministered i.v.


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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 ofpulmonary 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 longterm aspirin therapy.Fibrinolytics have no

role in chronic peripheral vascular diseases.


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ANTIFIBRINOLYTICS

These are drugs which inhibit plasminogenactivation and dissolution of clot.

EPSILON AMINO-CAPROIC ACID (EACA),TRANEXAMIC ACID, APROTININ:

Clinicaluses: they are administered by i.v. infusionin:

-overdose of streptokinase/ urokinase/alteplase;

-certain traumatic and surgical bleedings;- after cardio-pulmonary bypass surgery;

- after prostatic surgery , tooth extraction


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3. ANTIPLATELET DRUGS


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They interfere with platelet function and may be

useful in the prophylaxis of thromboembolic disorders.

-Antiplatelet drugs are more useful in arterialthrombosis while anticoagulants are more effective invenous thrombosis.

Drugs interfering with platelet function are:

*ASPIRIN:

-it inhibits COX and TX-synthetase-inactivating themirreversiblythe result is inhibition of TxA2synthesis.Aspirin also inhibits PGI2 synthesis in vesselswall.!!However, since intimal cells can synthesize freshenzyme , activity returns rapidly.

-It is possible that at low doses ( 75-150 mg /day or 300 mgtwice weekly) TxA2 formation by platelets is selectivelysuppressed whereas higher doses( > 900 mg/day) maydecrease both TxA2 and PGI2 production.


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*DIPYRIDAMOLE

-it is a vasodilator which was introduced for anginapectoris;

-it inhibits phosphodiesterase and blocks uptake ofadenosine 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 withprosthetic heart valves. It is administered orally,150-300 mg/day.


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*TICLOPIDINE

It is a thienopyridine which alters surface receptors onplatelets 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 agonistslike collagen, thrombin, TxA2 , ADP etc. induce plateletaggregation.


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*ABCIXIMAB

-it is the Fab fragment of an antibody against GP

IIb/IIIa ;

-given along with aspirin and heparin during

coronary angioplastyit has markedly reduced

the incidence of restenosis, subsequent

myocardial infarction and death. It isadministered i.v.; it is very expensive.


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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 preventreinfarction; also prevents reocclusion after thrombolytic therapy),

*unstable angina,

*primary and secondary prevention of myocardial infarction ( aspirin 75-150mg/day given to all individuals with evidence of coronary artery diseaseand in those with risk factors for the same).

-cerebrovascular disease( aspirin may reduce the incidence oftransient cerebral attacks in patients with persistent atrial fibrillation, or inthose with history of stroke).

-coronary bypass implants-incidenceof reocclusion is reduced byaspirin/ticlopidine/clopidrogel).

-prosthetic heart valves ;

-peripheral vascular disease-reducethe incidence ofthromboembolism.


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DRUGS USED IN ANAEMIAS


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These are agents required in the formationof blood and are used for treatment of

anaemias.

Anaemias occur when the balancebetween 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 , folicacid ; bone marrow depression ( hypoplasticanaemias ), erythropoietin deficiency.


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IRON

Iron has for long been considered important for thebody.

Distribution of iron in the body: total body iron in an adultis 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 andhaemosiderin ( 25%), myoglobin ( in muscles), parenchymaliron ( as constituent of enzymes) .

Daily requirement:adult male: 0,5-1 mg; adult female: 1-2mg; children: 25 g/kg.

Dietary sources of iron:rich: liver, egg yolk, dry beans, dryfruits; medium: meat, chicken, fish, spinach, banana,apple;poor: milk and its products.


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Preparations and dosages:

ORAL:some simple oral preparations are: ferrous sulfate,

ferrous gluconate, ferrous fumarate, colloidalferrichydroxide.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 tolower iron content.They are generally more expensive.


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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.


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PARENTERAL:iron-dextrane, iron-sorbitolcitric acidcomplex.They are administered deep i.m. , i.v. Iron therapyby 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 ( rheumathoidarthritis) etc.

-non-compliance to oral iron;

-in presence of severe deficiency with chronic bleeding.

Parenteral iron therapy needs calculation of the total ironrequirement 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, chestpain, metallic taste in the mouth, rare anaphylacticreaction.


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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 throatpain.


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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 bonemarrow and their large and shortlived

progeny in peripheral blood.The basic defect is

in DNA synthesis. Vitamin B12 and folic arecalled maturation factors.

VITAMIN B12


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VITAMIN B12

-cyancobalamin and hydroxocobalamin are complex

cobalt containing compounds present in diet andreferred as vit. B12.

-vitamin B12 occurs as water soluble , thermostablered crystals.It is synthesized in nature only bymicroorganisms ; 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. Thecommercial source is Streptomyces griseus.

Daily requirement: 1-3 g, pregnancy and lactation 3-5g.


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Deficiency of Vitamin B12 occurs due to:

-addisonian pernicious anaemia: is probably anautoimmune disorder which results in destruction of

gastric parietal cells absence of intrinsic factor ingastric juice ( along with achlohydria) inability toabsorb 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).


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Manifestations of deficiency:

-megaloblastic anaemia;

-glossitis;

-neurological: degeneration of spinal cord,

peripheral neuritis, poor memory, mood

changes etc.

P ti d d i i t ti


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Preparations, dose , administration:

CYANCOBALAMIN, HYDROXOCOBALAMIN,METHYLCOBALAMIN

They are administered parenterally ( i.m. / deep s.c.)/orally. Parenteral administration is necessary when B12deficiency is due to lack of intrinsic factor. Initially 30-100 g / day for 10 days followed by 100 g weekly and

then monthly for maintenance ( for life long).When neurological complications are present higherdoses 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.


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Clinical uses:

-treatment of vit. B12 deficiency: B12 is used asoutlined before. It is used in combination with iron and

with folic acid.Response to B12 is rapidsymptomaticimprovement starts in 2 days , mucosal lesions heal in1-2 weeks.Neurological parameters improve moreslowly-may be several months; full recovery may notoccur if vit. B12 deficiency has been sever or hadpersisted for long.

-mega doses of Vit. B12 have been used inneuropathies , psychiatric disorders and as a generaltonic to allay fatigue, improve growth.

Side effects:allergic reactionshave occurred ininjections; anaphylactoid reactions have occurred oni.v. injection ( this route should not be used).

FOLIC ACID


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FOLIC ACID

It occurs as yellow crystals which are insoluble inwater 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 forabsorbtion.

Daily requirement of an adult: < 0.1 mg but dietaryallowance of 0.2 mg / day is recommended.

During pregnancy , lactation or any condition ofhigh metabolic activity, 0.8 mg/day is consideredappropriate.

f f l d f d


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Deficiency:folate deficiency occurs due to:

Inadequate dietary intake;

Malabsorbtion: especially involving upperintestine;

Chronic alcoholism;

Increased demand: pregnancy, lactation, rapidgrowth periods, haemolyitic anaemia.

Drug induced: prolonged therapy withanticonvulsants ( phenytoin, phenobarbitone),

oral contraceptives-interfere with absorbtionof folate.


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Manifestations of deficiency:

Megaloblastic anemia, indistinguishable from that dueto B12 deficiency.However, folate deficiency developsmore rapidly if external supply is cut off: body storeslast 3-4 months only.

Epithelial damage: glossitis, enteritis, diarrhoea.

General debility, weight loss, sterility.

Preparations , dosages: FOLIC ACIDliquid oral preparations , injectables are

available only in combination formulations ( with B12,other vitamins) .

Oral therapy is adequate except when malabsorbtion ispresent or in severely ill patient-given i.m. Dose:therapeutic 2 to 5 mg /day , prophylactic 0,5 mg/day.


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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 whenpredisposing 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.

l3 Anticoagulants, Diuretics , Antidiuretics

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