Oral Anticoagulants

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

A haemorrhagic disease was described in cattle in 1924 which was due to feeding them on spoiled sweet clover hay. The disorder was found to be due to prothrombin deficiency and the toxic principle was identified as bis-hydroxycoumarin in 1939.


ORAL ANTICOAGULANTS

 

A haemorrhagic disease was described in cattle in 1924 which was due to feeding them on spoiled sweet clover hay. The disorder was found to be due to prothrombin deficiency and the toxic principle was identified as bis-hydroxycoumarin in 1939. It was cured by feeding alfalfa grass. First clinical use of bis-hydroxycoumarin was made in 1941 and many congeners were added later. Warfarin was initially used as rat poison; demonstration of its safety led to clinical trial; it is now a commonly employed oral anticoagulant.

 

 

Action And Mechanism

 

Warfarin and its congeners act as anticoagulants only in vivo, not in vitro. This is so because they act indirectly by interfering with the synthesis of vit K dependent clotting factors in liver. They apparently behave as competitive antagonists of vit K and reduce the plasma levels of functional clotting factors in a dose-dependent manner. In fact, they interfere with regeneration of the active hydroquinone form of vit K (Fig. 44.2) which carries out the final step of γ carboxylating glutamate residues of prothrombin and factors VII, IX and X. This carboxylation is essential for the ability of the clotting factors to bind Ca2+ and to get bound to phospholipid surfaces, necessary for coagulation sequence to proceed.

 


 

Factor VII has the shortest plasma t½ (6 hr), its level falls first when warfarin is given, followed by factor IX (t½ 24 hr), factor X (t½ 40 hr) and prothrombin (t½ 60 hr). Though the synthesis of clotting factors diminishes within 2–4 hours of warfarin administration, anticoagulant effect develops gradually over the next 1–3 days as the levels of the clotting factors already present in


plasma decline progressively. Thus, there is always a delay between administration of the drug and the anticoagulant effect. Larger initial doses hasten the effect only slightly.

 

Therapeutic effect occurs when synthesis of clotting factors is reduced by 40–50%.

 

Protein C, protein S, osteocalcin and some other proteins contain glutamate residues that require vit. K dependent carboxylation. These are also inhibited by oral anticoagulants, but density of adult bone is not affected, though new bone formation may be depressed.

 

The differences between different oral anticoagulants are primarily pharmacokinetic and in the adverse side effects produced by them. These are summarized in Table 44.1.

 


 

Recemic Warfarin sod. It is the most popular oral anticoagulant. The commercial preparation of warfarin is a mixture of R (dextrorotatory) and S (levorotatory) enantiomers. The S form is more potent and is metabolized relatively faster by ring oxidation, while R form is less potent and degraded by side chain reduction. Both are partially conjugated with glucuronic acid and undergo some enterohepatic circulation; finally excreted in urine.

 

Warfarin is rapidly and completely absorbed from intestines and is 99% plasma protein bound. It crosses placenta and is secreted in milk; however, quantity of active form is generally insufficient to affect the suckling infant.

 

UNIWARFIN 1, 2, 5 mg tabs; WARF5: 5 mg tab.

 

Bishydroxycoumarin (Dicumarol) It is slowly and unpredictably absorbed orally. Its metabolism is dose dependent—t½ is prolonged at higher doses. Has poor g.i. tolerance.

 

DICOUMAROL 50 mg tab.

 

Acenocoumarol (Nicoumalone) The t½ of acenocoumarol as such is 8 hours, but an active metabolite is produced so that overall t½ is about 24 hours. Acts more rapidly.

 

ACITROM, 1, 2, 4 mg tabs.

 

Ethyl biscoumacetate It has a rapid and brief action; occasionally used to initiate therapy, but difficult to maintain.

 

Phenindione It produces more serious nonhaemorrhagic toxic effects: should not be used.

 

DINDEVAN 50 mg tab.

 

Adverse Effects

 

Bleeding as a result of extension of the desired pharmacological action is the most important problem: ecchymosis, epistaxis, hematuria, bleeding in the g.i.t. Intracranial or other internal haemorrhages may be fatal. This is more likely if therapy is not properly monitored or interacting drugs/contraindications are present.

 

Treatment: of bleeding due to oral anticoagulants consists of:

 

·      Withhold the anticoagulant.

·  Give fresh blood transfusion: supplies clotting factors and replenishes lost blood. Alternatively fresh frozen plasma may be used as a source of clotting factors.

·   Give vit K1—specific antidote, but it takes 6–24 hours for the clotting factors to be resynthesized and released in blood after vit K administration.

 

Adverse effects unrelated to anticoagulation are given in Table 44.1. Cutaneous necrosis is a rare complication that can occur with any oral anticoagulant.

Phenindione produces serious toxicity; should not be used (though still available).

Warfarin and acenocoumarol are considered to be the most suitable and better tolerated drugs.

 

Dose Regulation

 

The dose of oral anticoagulant must be individualised by repeated measurement of prothrombin time; the aim is to achieve a therapeutic effect without unduly increasing the chances of bleeding.

 

The optimum ratio of PT during treatment to the normal value (of the testing laboratory) has been defined for various indications. But this value differs depending on whether rabbit brain or human brain thromboplastin (Tp) has been used for the test. A standardized system called the International Normalized Ratio (INR) based on the use of human brain Tp has been developed by WHO and adopted in all countries.

 


 

Factors enhancing effect of oral anticoagulants are:

 

·    Debility, malnutrition, malabsorption and prolonged antibiotic therapy: the supply of vit K to liver is reduced in these conditions.

·    Liver disease, chronic alcoholism: synthesis of clotting factors may be deficient.

·    Hyperthyroidism: the clotting factors are degraded faster.

·    Newborns: have low levels of vit K and clotting factors (there should be no need of these drugs in neonates anyway).

 

Factors decreasing effect of oral anticoagulants are:

 

·    Pregnancy: plasma level of clotting factors is higher.

·    Nephrotic syndrome: drug bound to plasma protein is lost in urine.

·    Genetic warfarin resistance: the affinity of warfarin (as well as of vit K epoxide) to bind to the reductase enzyme, which generates the active vit K hydroquinone, is low. Dose of oral anticoagulant is 4–5 times higher.

 

Contraindications

 

All contraindications to heparin apply to these drugs as well. Factors which enhance the effect of oral anticoagulants (see above) should also be taken into consideration.

 

Oral anticoagulants should not be used during pregnancy. Warfarin given in early pregnancy increases birth defects, especially skeletal abnormalities: foetal warfarin syndrome—hypoplasia of nose, eye socket, hand bones, and growth retardation. Given later in pregnancy, it can cause CNS defects, foetal haemorrhage, foetal death and accentuates neonatal hypoprothrombinemia.

 

Drug Interactions

 

A large number of drugs interact with oral anticoagulants at pharmacokinetic or pharmacodynamic level, and either enhance or depress their effect. These interactions are clinically important (may be fatal if bleeding occurs) and may involve more than one mechanism; the exact mechanism of an interaction is not always definable.

 

A. Enhanced Anticoagulant Action

 

1.   Broad spectrum antibiotics, inhibit gut flora and reduce vit K production.

2. Newer cephalosporins (cefamandole, moxalactam, cefoperazone) cause hypo-prothrombinaemia by the same mechanism as warfarin —additive action.

3.   Aspirin: inhibits platelet aggregation and causes g.i. bleeding—this may be hazardous in anticoagulated patients. High doses of salicylates have synergistic hypo-prothrombinemic action and also displace warfarin from protein binding site.

4.   Long acting sulfonamides, indomethacin, phenytoin and probenecid: displace warfarin from plasma protein binding.

5. Chloramphenicol, erythromycin, celecoxib, cimetidine, allopurinol, amiodarone and metronidazole: inhibit warfarin metabolism.

6.   Tolbutamide and phenytoin: inhibit warfarin metabolism and vice versa.

7.   Liquid paraffin (habitual use): reduces vit K absorption.

 

B. Reduced Anticoagulant Action

 

1.  Barbiturates (but not benzodiazepines), rifampin and griseofulvin induce the metabolism of oral anticoagulants. The dose of anticoagulant determined during therapy with these drugs would be higher: if the same is continued after withdrawing the inducer— marked hypoprothrombinemia can occur— fatal bleeding is on record.

2.   Oral contraceptives: increase blood levels of clotting factors.

 

Uses Of Anticoagulants

 

The aim of using anticoagulants is to prevent thrombus extension and embolic complications by reducing the rate of fibrin formation. They do not dissolve already formed clot, but prevent recurrences. Heparin is utilized for rapid and shortlived action, while oral anticoagulants are suitable for maintenance therapy. Generally, the two are started together; heparin is discontinued after 4–7 days when warfarin has taken effect.

 

The important features of heparin and oral anticoagulants are compared in Table 44.2.

 


 

Deep Vein Thrombosis And Pulmonary Embolism

 

Because venous thrombi are mainly fibrin thrombi, anticoagulants are expected to be highly effective. The best evidence of efficacy of anticoagulants comes from treatment and prevention of venous thrombosis and pulmonary embolism. Prophylaxis is recommended for all high risk patients including bedridden, old, postoperative, postpartum, poststroke and leg fracture patients. When deep vein thrombosis/ pulmonary embolism has occurred, immediate heparin followed by warfarin therapy should be instituted. Three months anticoagulant therapy (continued further if risk factor persists) has been recommended by American College of Chest Physicians (2001).

 

Introduction of low dose heparin prophylaxis for patients undergoing elective surgery has considerably reduced the incidence of leg vein thrombosis and pulmonary embolism in the postoperative period. It has been extended to other situations needing prolonged immobilization. It is based on the premise that inhibition of small amount of activated factor X prevents further amplification of active products—particularly thrombin. This is the regimen of choice: does not need laboratory monitoring; spontaneous bleeding does not occur. LMW heparin is being preferred for this purpose. Anticoagulants are of little value in chronic peripheral vascular diseases.

 

Myocardial Infarction (MI)

 

Arterial thrombi are mainly platelet thrombi; anticoagulants are of questionable value. Their use in acute MI has declined. They do not alter immediate mortality of MI. It was hoped that anticoagulants will prevent extension of the thrombus and ward off a recurrent attack. This has not been supported by the collected statistics. They may benefit by preventing mural thrombi at the site of infarction and venous thrombi in leg veins. Thus, anticoagulants may be given for a short period till patient becomes ambulatory. 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. Heparin is also used during coronary angioplasty and stent placement.

 

Unstable Angina

 

Short-term use of heparin has reduced the occurrence of MI in unstable angina patients; aspirin is equally effective.

Current recommendation is to use aspirin + heparin followed by warfarin.

 

Rheumatic Heart Disease; Atrial Fibrillation (AF)

 

Warfarin/low dose heparin/low dose aspirin are effective in preventing stroke (due to embolism from fibrillating atria). The ‘Stroke prevention in Atrial Fibrillation’ trial and a meta-analysis have shown warfarin to be more effective than aspirin. Current guideline is to give warfarin to a target INR of 2–3 in AF patients with high risk for stroke (elderly, heart failure, etc.), and to reserve aspirin for low risk patients or for those unable to take warfarin. Anticoagulants are given for 3–4 weeks before and after attempting conversion of AF to sinus rhythm.

 

Cerebrovascular Disease

 

Anticoagulants are of little value in cerebral thrombosis. They have been used with the aim of preventing clot propagation, but all the trials conducted, including International Stroke Trial (IST), have failed to demonstrate significant benefit. Neurological sequelae are similar whether they are used or not. Moreover, in the initial stages it is difficult to rule out cerebral haemorrhage (unless CAT scan is done) in which they can be devastating. They may be used in cerebral embolism, because showers of emboli are often recurrent and can be prevented by anticoagulants. A late start (after one week) anticoagulant therapy is advocated by many in case of large embolic stroke. Oral anticoagulants may be beneficial in transient ischaemic attacks (TIAs), but antiplatelet drugs are simpler to use and probably better.

 

Vascular Surgery, Prosthetic Heart Valves, Retinal Vessel Thrombosis, Extracorporeal Circulation, Haemodialysis

 

Anticoagulants are indicated along with antiplatelet drugs for prevention of thromboembolism.

 

Heparin flushes (200 U in 2 ml) every 4–8 hr are used to keep patent long-term intravascular cannulae/catheters.

 

Defibrination Syndrome  

 

‘Disseminated intravascular coagulation’ occurs in abruptio placentae and other obstetric conditions, certain malignancies and infections. The coagulation factors get consumed for the formation of intravascular microclots and blood is incoagulable. Heparin paradoxically checks bleeding in such patients by preserving the clotting factors. However, in some cases heparin may aggravate bleeding.

 

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