Coagulants

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Chapter: Essential pharmacology : Drugs Affecting Coagulation, Bleeding And Thrombosis

These are substances which promote coagulation, and are indicated in haemorrhagic states.


COAGULANTS

 

These are substances which promote coagulation, and are indicated in haemorrhagic states.

 

Fresh whole blood or plasma provide all the factors needed for coagulation and are the best therapy for deficiency of any clotting factor; also they act immediately. Other drugs used to restore haemostasis are:

 

1. Vitamin K

K1 (from plants, : Phytonadione

fatsoluble)        (Phylloquinone)

 

K3 (synthetic)

Fatsoluble      : Menadione, Acetomenaphthone

Watersoluble :  Menadione sod. Bisulfite

                       :  Menadione sod. diphosphate

 

2. Miscellaneous

 

Fibrinogen (human)

Antihaemophilic factor

Desmopressin

Adrenochrome monosemicarbazone

Rutin,

Ethamsylate

 

VITAMIN K

 

It is a fatsoluble dietary principle required for the synthesis of clotting factors.

 


 

Dam (1929) produced bleeding disorder in chicken by feeding deficient diet. This was later found to be due to decreased concentration of prothrombin in blood and that it could be cured by a fat soluble fraction of hog liver. This factor was called Koagulations vitamin (vit K) and soon its structure was worked out. A similar vitamin was isolated in 1939 from alfalfa grass and labelled vit K1, while that from sardine (sea fish) meal was labelled K2. Synthetic compounds have been produced and labelled K3.

 

Chemistry And Source

 

Vit K has a basic naphthoquinone structure, with or without a side chain (R) at position 3. The side chain in K1 is phytyl, in K2 prenyl, while in K3 there is no side chain.

 

Dietary sources are—green leafy vegetables, such as cabbage, spinach; and liver, cheese, etc.

 

Daily Requirement

 

It is uncertain, because a variable amount of menaquinone (vit K2) produced by colonic bacteria becomes available. Even 3–10 μg/day external source may be sufficient. However, the total requirement of an adult has been estimated to be 50–100 μg/day.

 

Action

 

Vit K acts as a cofactor at a late stage in the synthesis by liver of coagulation proteins— prothrombin, factors VII, IX and X. The vit K dependent change (γ carboxylation of glutamate residues of these zymogen proteins; see Fig. 44.2) confers on them the capacity to bind Ca2+ and to get bound to phospholipid surfaces—properties essential for participation in the coagulation cascade.

 

Utilization

 

Fat-soluble forms of vit K are absorbed from the intestine via lymph and require bile salts for absorption, while water-soluble forms are absorbed directly into portal blood. An active transport process in the jejunum has been demonstrated for K1, while K2 and K3 are absorbed by simple diffusion. Vit K is only temporarily concentrated in liver, but there are no significant stores in the body. It is metabolized in liver by side chain cleavage and glucuronide conjugation; metabolites are excreted in bile and urine.

 

Deficiency

 

Deficiency of vit K occurs due to liver disease, obstructive jaundice, malabsorption, long-term antimicrobial therapy which alters intestinal flora. However, deficient diet is rarely responsible. The most important manifestation is bleeding tendency due to lowering of the levels of prothrombin and other clotting factors in blood. Haematuria is usually first to occur; other common sites of bleeding are g.i.t., nose and under the skin—ecchymoses.

 

Preparations

 

Phytonadione: VITAMINK, KENADION 10 mg/ml for i.m. injection.

 

Menadione: 0.66 mg in GYNAE CVP with vit C 75 mg, ferrous gluconate 67 mg, Cal. lactate 300 mg and citras bioflavonoid 150 mg per cap:

 

Acetomenaphthone: ACETOMENADIONE 5, 10 mg tab; KAPILIN 10 mg tab.

 

Menadione sod. bisulfite: 20 mg, in CADISPERC with vit C 100 mg, adrenochrome monosemicarbazone, 1 mg, rutin 60 mg, methylhesperidin 40 mg, Cal. phosphate 100 mg per tab.


STYPTOCID 10 mg with adrenochrome monosemicarbazone 0.5 mg, rutin 50 mg, vit C 37.5 mg, vit D 200 i.u., Cal. phosphate 260 mg per tab.

 

Use

 

The only use of vit K is in prophylaxis and treatment of bleeding due to deficiency of clotting factors in the following situations:

 

a)   Dietary Deficiency: of vit K is very rare in adults. However, when it occurs 5–10 mg/day oral or parenteral vit K rapidly corrects the defects.

 

b)     Prolonged Antimicrobial Therapy: treat in the same way as dietary deficiency of vit K.

 

c) Obstructive Jaundice Or Malabsorption Syndromes (sprue, regional ileitis, steatorrhoea, etc.): vit K 10 mg i.m./day, or orally along with bile salts.

 

d)    Liver Disease (Cirrhosis, Viral Hepatitis): associated bleeding responds poorly to vit K. Because of hepatocellular damage, synthesis of clotting factors is inadequate despite the presence of vit K. However, vit K may be of some use if its absorption had been affected due to lack of bile salts.

 

e)   Newborns: All newborns have low levels of prothrombin and other clotting factors. Further decrease occurs in the next few days. The cause is both lower capacity to synthesize clotting factors as well as deficiency of vit K. The defect is exaggerated in the premature infant. Vit K 1 mg i.m. soon after birth has been recommended routinely. Some prefer administering 5–10 mg i.m. to the mother 4–12 hours before delivery. Haemorrhagic disease of the newborn can be effectively prevented/treated by such medication.

 

Menadione (K3) should not be used for this purpose (see below).

 

f)    Overdose Of Oral Anticoagulants: This is the most important indication of vit K. Phytonadione (K1) is the preparation of choice, because it acts most rapidly; dose depends on the severity of hypo-prothrombinaemia (measured INR) and bleeding. Unnecessary high dose is to be avoided because it will render the patient unresponsive to oral anticoagulants for several days.

 

Severe: 10 mg i.m. followed by 5 mg 4 hourly; bleeding generally stops in 6–12 hours, but normal levels of coagulation factors are restored only after 24 hr. This dose of vit-K will block anticoagulant action for 7–10 days.

 

Moderate: 10 mg i.m. followed by 5 mg once or twice according to response.

 

Mild: Just omit a few doses of the anticoagulant.

 

g) Prolonged high dose salicylate therapy causes hypoprothrombinemia; vit K should be given prophylactically. If bleeding occurs—treat as for oral anticoagulants.

 

Toxicity

 

Rapid i.v. injection of emulsified vit K produces flushing, breathlessness, a sense of constriction in the chest, fall in BP; few deaths are on record. It is probably due to emulsion form of the preparation.

 

Menadione and its watersoluble derivatives can cause haemolysis in a dosedependent manner. Patients with G6PD deficiency and neonates are especially susceptible. In the newborn menadione or its salts can precipitate kernicterus:

 

·      by inducing haemolysis and increasing bilirubin load.

·      by competitively inhibiting glucuronidation of bilirubin. Glucuronide conjugation is, as such, inadequate in neonates.

 

Because of poor efficacy and higher toxicity, there is little justification to use menadione and its water-soluble salts for any indication.

 

Fibrinogen

 

The fibrinogen fraction of human plasma is employed to control bleeding in haemophilia, antihaemophilic globulin (AHG) deficiency and acute afibrinogenemic states; 0.5 g is infused i.v.

FIBRINAL 0.5 g/bottle for i.v. infusion.

 

Antihaemophilic Factor

 

It is concentrated human AHG prepared from pooled human plasma. It is indicated (along with human fibrinogen) in haemophilia and AHG deficiency. It is highly effective in controlling bleeding episodes, but action is shortlasting (1 to 2 days).

 

Dose: 5–10 U/kg by i.v. infusion, repeated 6–12 hourly.

 

FIBRINALH, ANTIHAEMOPHILIC FACTOR: 150 U or 200 U + fibrinogen 0.5 g/bottle for i.v. infusion.

 

Desmopressin

 

It releases factor VIII and von Willebrand’s factor from vascular endothelium and checks bleeding in haemophilia and von Willebrand’s disease.

 

Adrenochrome Monosemicarbazone

 

It is believed to reduce capillary fragility, control oozing from raw surfaces and prevent microvessel bleeding, e.g. epistaxis, haematuria, retinal haemorrhage, secondary haemorrhage from wounds, etc. Its efficacy is uncertain.

Dose: 1–5 mg oral, i.m.

 

STYPTOCHROME 3 mg/2 ml inj., STYPTOCID: 2 mg/2 ml inj; in CADISPERC, STYPTOCID 1 mg, 0.5 mg tab, with other ingredients.

 

Rutin

 

It is a plant glycoside claimed to reduce capillary bleeding. It has been used in a dose of 60 mg oral BD–TDS along with vit C which is believed to facilitate its action. Its efficacy is uncertain.

 

In CADISPERC 60 mg tab, in KERUTINC 100 mg tab, in STYPTOBION 100 mg tab, 200 mg/2 ml inj.

 

Ethamsylate

 

It reduces capillary bleeding when platelets are adequate; probably exerts anti-hyaluronidase action— improves capillary wall stability, but does not stabilize fibrin (not an antifibrinolytic). Ethamsylate has been used in the prevention and treatment of capillary bleeding in menorrhagia, after abortion, PPH, epistaxis, malena, hematuria and after tooth extraction, but efficacy is unsubstantiated. Side effects are nausea, rash, headache, and fall in BP (only after i.v. injection).

 

Dose: 250–500 mg TDS oral/i.v.; ETHAMSYL, DICYNENE, HEMSYL, K. STAT 250, 500 mg tabs; 250 mg/2 ml inj.

 

LOCAL HAEMOSTATICS (STYPTICS)

 

After injury to arterioles and other smaller blood vessels, normal haemostasis occurs successively by contraction of injured vessel wall (lasting few minutes), adhesion and aggregation of platelets to form a plug, formation of a blood clot, and finally in due course dissolution of the clot by fibrinolysis. External bleeding is usually stopped by manual pressure, cotton gauze pressure pack or by suturing. Control of bleeding may be aided by local haemostatics (styptics) that are substances used to stop bleeding from a local and approachable site. They are particularly effective on oozing surfaces, e.g. tooth socket, abrasions, etc. Absorbable materials like fibrin (prepared from human plasma and dryed as sheet or foam), gelatin foam, oxidized cellulose (as strips which can be cut and placed in the wound) provide a meshwork which activates the clotting mechanism and checks bleeding. Left in situ these materials are absorbed in 1–4 weeks and generally cause no foreign body reaction. Thrombin obtained from bovine plasma may be applied as dry powder or freshly prepared solution to the bleeding surface in haemophiliacs.

 

Vasoconstrictors like 0.1% Adr solution may be soaked in sterile cotton gauze and packed in the bleeding tooth socket or nose in case of epistaxis to check bleeding when spontaneous vasoconstriction is inadequate. Astringents such as tannic acid or metallic salts are occasionally applied for bleeding gums, bleeding piles, etc.

 

SCLEROSING AGENTS

 

These are irritants, cause inflammation, coagulation and ultimately fibrosis, when injected into haemorrhoids (piles) or varicose vein mass. They are used only for local injection.

 

1. Phenol (5%) in almond oil or peanut oil: 2–5 ml.

2. Ethanolamine oleate (5% in 25% glycerine and 2% benzyl alcohol): 1–5 ml inj.

3. Sod. tetradecyl sulfate (3% with benzyl alcohol 2%): 0.5–2 ml at each site. SETROL 2 ml inj.

4. Polidocanol (3% inj): 2 ml; ASKLEROL 2 ml inj.

 

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