Anticoagulants

by

Haider zamanMedical Lab Technology

Coagulation

•Coagulation =(also known as clotting)

• is the process by which blood changes from a liquid to a gel, forming a clot.

Anticoagulants• A substance that prevents blood from clotting by suppressing the

synthesis or function of various clotting factors.

• Anticoagulants are given to prevent thrombosis and used in drawing and storing blood.

• There are two main types of anticoagulants:

Heparin

vitamin K antagonists (e.g., warfarin).

Heparin

• Heparin is a naturally-occurring anticoagulant produced by basophils and mast cells.

• Heparin acts as an anticoagulant, preventing the formation of clots and extension of existing clots within the blood. While heparin does not break down clots that have already formed (unlike tissue plasminogen activator), it allows the body's natural clot lysis

• Highly ionized, not absorbed orally.

• it is given IV only.

• Heparin is one of the oldest drugs currently in widespread clinical use. It was originally isolated from canine liver cells, hence its name Heparin.

Heparin structure

• heparin is heterogeneous of un branched polysaccharide chains

Alternating monosaccharide units of L-iduronic acid and D-glucosamine

• one third of the polysaccharide chain contain a specific antithrombin binding pentasaccharide sequence

Source

preparation from porcine and bovine intestinal mucous

preparation from bovine lung

Heparin Actions

Heparin exerts parts of its anticoagulant activity through interaction with antithrombin

antithrombin binds specifically to a pentsaccharide in heparin

binding to heparin induced a conformational change in the antithrombin , which accelerate enzyme inhibition

Heparin mechanism of action

Heparin

Antithrombin IIIThrombin

Adverse effects of Heparin

1. Bleeding due to overdose – hematuria is 1st sign

2. Thrombocytopenia – aggregation of platelets

3. Hypersensitivity – urticaria, rigor, fever and anaphylaxis etc.

4. Alopecia and osteoporosis

• Contraindications: Bleeding disorders, Severe hypertension, GIT ulcer, Piles, SABE & malignancy, Ocular & neurosurgery, Chronic alcoholism, cirrhosis etc.

• Aspirin and antiplatelet drugs - caution

Pharmacokinetics Heparin

Absorption: Heparin is not absorbed from GI; must be given IV or subcutaneously,

Metabolism: The liver and reticuloendothelial system are the sites of biotransformation.

Elimination: The average half-life is 1.5 h(range, 1 to 6 h) and is dose dependent Excreted in theurine

Dosage and Administration:

intravenously (immediate effect)- 20 to 40 thousands units/day dose

subcutaneously ( effect on 20-60 min )-8,000 to 10,000 units every 8 h .

Drug interactions

• interaction with :

• Alteplase

• Antihistamines

• Antithrombin

• Cephalosporins (eg, cefazolin, ceftriaxone)

• Penicillins, parenteral (eg, ampicillin, penicillin G)

Warfarin

Warf Warfarin is an oral anticoagulant widely used to control and prevent thromboembolic disorders.

Warfarin is clinically available as a racemic mixture of R- and S-warfarin. The S-enantiomer has 3–5 times greater anticoagulation potency than its optical congener R-warfarin.

Action of Warfarin

Warfarin acts by antagonizing the anti- hemorrhagic effect of vitamin K.

It inhibits hepatic synthesis of vitamin K dependent coagulation factors II, VII, IX, and X by inhibiting vitamin K1 -2,3 epoxide reductase

preventing vitamin K from being reduced to its active form.

Pharmacokinetic

The oral bioavailability of warfarin is nearly 100%.

It is highly bound (approximately 99%) to plasma protein, mainly albumin. (The high degree of protein binding is one of several mechanisms whereby other drugs interact with warfarin)

Warfarin is distributed to the liver, lungs, spleen, and kidneys. It does not appear to be distributed to breast milk in significant amounts. It crosses the placenta and is a known teratogen.

The duration of anticoagulant effect after a single dose of warfarin is usually 5-7 days.

Pharmacokinetic

Warfarin is metabolized by hepatic cytochrome P-450 (CYP) isoenzyme to inactive metabolites, which are excreted in the bile. (It also is metabolized by reductases to reduced metabolites “warfarin alcohols” , which are excreted in the kidneys).

Warfarin metabolism may be altered in the presence of hepatic dysfunction or advanced age but is not affected by renal impairment.

Indications

prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.

prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.

to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Dosage and Administration

Adults: PO 2-5 mg/day initially; adjust daily dose according to PT or INR determinations. Usual maintenance dose is 2-10 mg/day.

The IV dosages would be the same as those would be used orally. Administer as a slow bolus injection over 1 to 2 min in a peripheral vein.

Adverse Effects

Hematologic: hemoptysis, bruising, epistaxis, bleeding gums, hematouriaor blood in stool.

Cardiovascular: hypotension, syncope, vasculitis.

CNS: dizziness, fatigue, headache, lethargy.

Hepatic: elevated liver enzymes, hepatitis, jaundice.

Miscellaneous: hypersensitivity reactions, osteoporosis, chest pain, fever, purple toe syndrome.

Drug Interactions

Divided into:

1. Pharmacokinetic mechanisms:

1) enzyme induction 2) enzyme inhibition 3) reduced plasma protein binding.

2. Pharmacodynamic mechanisms:

1) synergism 2) competitive antagonism (vit K) 3) an altered physiologic control for vitamin K (hereditary resistance to oral anticoagulants).