Clinical pharmacology

Blood coagulation & Anticoagulants
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Contents
• • • • • • • Blood coagulation Anticoagulants Classes of Anticoagulants Uses of anticoagulants Indirect-acting Direct-acting Surgery in patients receiving anticoagulant therapy • The use of anticoagulants in pregnancy

Blood coagulation
Blood coagulation means the conversion of fluid blood to a solid gel or clot. The main event is the conversion of soluble fibrinogen to insoluble strands of fibrin by thrombin ,which is the last step in a complex enzyme cascade.

Coagulation Cascade
Intrinsic Pathway (vessel wall damage) XIIa12 XIa11 IXa9
Xa & V Prothrombin

Extrinsic Pathway (damaged tissue )

VIIa7
tissuethrom boplastin

Heparin / LMWH

Thrombin (IIa) Thrombin-Fibrin Clot

Anticoagulants
An anticoagulant is a substance that prevents coagulation. Anticoagulants can be used in vivo as a medication for thrombotic disorders. Some chemical compounds ( e.g. EDTA )are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis equipment.

Classes of Anticoagulants
• Indirect-acting: the coumarin derevatives drugs (e.g. warfarin) take about 72 h to become fully effective, act for several days, are given orally or by injec.. • Direct-acting: heparin and LMW heparin are rapidly effective, and available parenterally.

Uses of anticoagulants
Generally, these anticoagulants are used to treat patients with 1-deep-vein thrombosis (DVT) 2- pulmonary embolism (PE) 3- atrial fibrillation (AF) 4-and mechanical prosthetic heart valves.

Indirect-acting
Warfarin is a synthetic derivative of coumarin, it is a Vitamin K antagonists. it is readily absorbed from the GIT and more than 90% bound to plasma protein.

Mechanism of action
It is structurlly similar to vit K & competitively inhibit epoxide reductase that is responsible for the reactivation of vit K to form coagulant factors(2,7,9,10 & anticoagulant protein c & s).
**Vit K interfere with the carboxylation of glutamic acid residues in clotting factors II, VII, IX and X..

Mechanism of action
In active factors 2,7,9,10,& protein c & s. Activated clotting factors

Reduced Vitamin K Oxidized Vitamin K
NAD
epoxide reductase

NADH

Warfarin

Onset of action of warfarin
The effect takes several days to develop because of the time taken for degradation of preformed carboxylated clotting factors. The onset of action thus depends on the elimination half-lives of the relevant factors. Factor VII, with a half-life of 6 hours, is affected first, then IX, X and II, with half-lives of 24, 40 and 60 hours, respectively

Dose of warfarin
There is much inter-individual variation in dose requirements. The usual dose to initiate therapy is 5-10 mg daily for 2 days, with the maintenance dose then adjusted according to the INR. • 1. INR 2.0-2.5 Prophylaxis of deep vein thrombosis • 2. INR 2.0-3.0 treatment of DVT & pulmonary embolism. • 3. INR 3.0-4.5 recurrent DVT & pulmonary embolism .

MONITORING OF ANTICOAGULANT THERAPY
MONITORING OF ANTICOAGULANT THERAPY by INR ( international normalized ratio ), which is the ratio of prothrombin time in the patient to that in a normal (un-anticoagulated) person.

Adverse effects of warfarin
1. Bleeding (4-8%). 2. Cutaneous reactions: apart from purpura and ecchymoses, in those who are excessively anticoagulated; & skin necrosis due to a mixture of haemorrhage and thrombosis occurs rarely where induction of warfarin therapy is abrupt and/or the patient has a genetically detemined deficiency of the anticoagulant protein c & s .

Adverse effects of warfarin … cont.

3. Warfarin used in early pregnancy may injure the fetus (other than by *bleeding). It causes *skeletal disorder (5%) (bossed forehead, sunken nose) and *absence of the spleen. *CNS abnormalities are reported with warfarin used at any stage of pregnancy and are presumed to be due to intracranial hemorrhage.

Adverse effects of warfarin …cont.

4. Another rare complication that may occur early during warfarin treatment (usually within 3 to 8 weeks) is purple toe syndrome. This condition is thought to result from small deposits of cholesterol breaking and flowing into the blood vessels in the skin of the feet, which causes a blueish purple color and may be painful.

Management of bleeding caused by warfarin
• Blood replacement, prothrombin complex concentrate(containing factor II, IX9 and X, and given i.v. as 50 units per kg of factor IX) or fresh frozen plasma. If full reversal of anticoagulation is judged necessary, 5 mg of Vit. K is then given by slow i.v. injection.

Management of bleeding caused by warfarin….CONT.

• for lesser bleeding, warfarin should be withheld and 0.5-2 mg of Vit.K may be given by slow i.v. injection. • INR> 7 but with out bleeding. Correct by withholding warfarin, and given 0.5 mg OF Vit.K by slow i.v. injection if judged appropriate. • INR 4.5-7.0 manage by with holding warfarin for 1-2 days and then reviewing the INR.

Drug Interactions
Increase risk of hemorrhage: 1- Decrease metabolism by amidarone , metronidazole , ciprofloxacin, erythromicine , cimetidine , INH & flouxitine . 2- Displacement from protein binding sites caused by loop diuretics and valproate. 3- Relative deficiency of vit K. 4-Excessive use of alcohol is also known to affect the metabolism of warfarin 5- Low concentration of coagulation factors as in -Hepatic failure -Hyperthyroidism -Congestive heart failure

Drug Interactions
*Decrease anticoagulant effect

1- Decrease absorption by cholystiramine in GIT. 2- Increase metabolism by barbiturate, carbamazepine, rifampicin. 3- There is a decreased response to warfarin in conditions (e.g. pregnancy) where there is increased coagulation factor synthesis. Similarly, the effect of oral anticoagulants is lessened in

Direct-Acting Anticoagulants: Heparin
Heparin isa naturally-occurring anticoagulant produced by basophils and mast cells. It is highly-sulfated glycosaminoglycan & can be used as an injectable anticoagulant. Heparin depends for its action on the presence of plasma protein, antithrombin III, which a naturally occurring inhibitor of thrombin and of activated factor X (Xa). in the

MONITORING OF ANTICOAGULANT THERAPY
• The activated partial thromboplastin time (APTT) used for detecting abnormalities in blood clotting, and to monitor the treatment effects with heparin. indicator measuring the efficacy of the "intrinsic“ pathway.

Adverse affects of heparin
1. Bleeding 2. The syndrome of thrombocytopenia (HIT syndrome) with arterial thromboemboli and hemorrhage which occurs in about 23٪ of patients who receive heparin for a week or more. 3. Warfarin should be substituted, if the platelet count falls when a patient receives heparin. 4. Osteoporosis. 5. Hypersensivity reactions and skin necrosis may occur but are rare.

Adverse affects of heparin…cont.

6. The other complication is hyperkalemia, which occurs in 5 to 10% of patients receiving heparin, and is the result of heparin-induced aldosterone suppression.

LMW heparins
• Are as effective and safe as conventional (unfractionated) heparin at preventing venous thrombosis.but They are eliminated mainly by renal excretion, and unfractionated heparin is preferred in renal failure. e.g. : - Dalteparin . - Dnoxaparin. - demiparin.

LMW heparins …cont

Low-molecular-weight heparins are given subcutaneously. They have a longer half-life than unfractionated heparin, so the effects are more predictable and dosing less frequent (once or twice a day). LMWHs do not prolong the APTT; unlike unfractionated heparin, the effect of a standard dose is sufficiently predictable that monitoring is not

Heparin LMWHs
• 15 - 100 monosaccharides per molecule • High affinity for plasma proteins • 30% bio-availability after subcutaneous injection • 4 - 40 monosaccharides per molecule • Low affinity for plasma proteins • 90% bio-availability after subcutaneous injection

Surgery in patients receiving anticoagulant therapy
For elective surgery warfarin may be withdrawn about 5 days before the operation and resumed about 3 days after if condition seems appropriate, low-dose heparin may be used in the intervening period. In patients with mechanical prosthetic valves, heparin is substituted at full dosage 4 days before surgery and restarted 12-14h after the operation. Warfarin is restarted when the patient resumes oral intake.

The use of anticoagulants in pregnancy
Women on long term warfarin should be advised not to become pregnant while taking the drug. Heparin should be substituted prior to conception and continued through the first trimester, after which warfarin should replace heparin, as continued exposure to heparin may cause osteoporosis. Warfarin should be discontinued near term as it exacerbates neonatal hypoprothrombinaemia .

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