Mechanism of Anticoagulant Action
Heparin does not directly affect coagulation factors. It works as a cofactor for the endogenous inhibitor antithrombin III (ATIII). For successful binding, the drug molecule must possess a unique pentasaccharide sequence, which is present in only about 30% of molecules in a standard mixture.
Upon binding to ATIII, heparin alters its spatial structure, which accelerates the inactivation of coagulation factors (especially thrombin and factor Xa) by approximately 1,000 times. The efficiency of this process directly depends on the length of the polysaccharide chain:
- Long chains (more than 18 monosaccharides, mass > 5,400 Da) act as a "bridge." They can simultaneously hold an ATIII molecule and thrombin (factor IIa), providing antithrombin activity.
- Short chains (fewer than 18 monosaccharides) cannot hold both molecules. They lack antithrombin action, but successfully activate ATIII to block factor Xa.
Standard unfractionated heparin contains predominantly long chains, thus inhibiting thrombin and factor Xa in equal proportions (1:1).
Pleiotropic (Non-Anticoagulant) Effects
In addition to interfering with the coagulation cascade, the drug possesses several additional pharmacological properties:
- Antiatherosclerotic effect: stimulates lipoprotein lipase release, accelerating triglyceride hydrolysis, and inhibits vascular smooth muscle cell proliferation.
- Anti-inflammatory effect: inhibits the enzyme hyaluronidase and reduces vascular wall permeability.
- Fibrinolytic activity: promotes the release of tissue plasminogen activator (tPA) from the endothelium.
- Effect on bone tissue and electrolytes: with prolonged use, it increases parathyroid hormone activity (increasing the risk of osteoporosis) and suppresses aldosterone synthesis (risk of hyperkalemia).
Pharmacokinetics and Routes of Administration
The drug is obtained by extraction from porcine intestinal mucosa or bovine lung. It is not administered orally (per os) due to a lack of absorption.
| Route of Administration | Onset of Action | Duration of Effect | Features |
|---|---|---|---|
| Intravenous | Immediate | 2–6 hours | Administered as a bolus or infusion |
| Subcutaneous | 1–2 hours | 8–12 hours | Calcium heparin is administered only subcutaneously |
The drug does not cross the placental barrier, making it safe for use during pregnancy. It is metabolized in the liver with the participation of the enzyme heparinase, and degradation products are excreted by the kidneys. With long-term therapy, tolerance may develop due to the depletion of endogenous antithrombin III reserves.
Side Effects and Overdose
The most frequent complication of therapy is bleeding. For mild overdose, withdrawing the drug is sufficient. For life-threatening hemorrhages, the specific antagonist protamine sulfate is administered intravenously, which chemically binds heparin into an insoluble complex.
Of particular danger is heparin-induced thrombocytopenia (HIT). It occurs in two forms:
- Early (benign): occurs on days 2–4, runs a mild course, and does not require discontinuation of therapy.
- Late (immune): develops on days 5–12. The body produces IgG antibodies against the complex of heparin and platelet factor 4. These antibodies damage the endothelium and cause massive platelet activation. A paradoxical reaction occurs: against the background of falling platelet counts, severe thrombosis develops (infarctions, strokes, gangrene). The condition requires immediate discontinuation of the drug and switching to alternative anticoagulants (e.g., lepirudin).
Topical Administration
The drug is widely used in the form of ointments and gels for local action. In combination products (e.g., with benzocaine and benzyl nicotinate), it provides antithrombotic, anti-edematous, and analgesic effects. The main indications for external use are subcutaneous hematomas, varicose veins, and superficial thrombophlebitis.