dextran 40 Clinical Pharmacology

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CLINICAL PHARMACOLOGY

The fundamental action of LMD (dextran 40) is the enhancement of blood flow, particularly in the microcirculation. This enhancement is due to:

1.
Its primary effect of volume expansion with resultant hemodilution;
2.
Maintenance of the electronegativity of red blood cells;
3.
Coating of red blood cells and platelets;
4.
Increase in the suspension stability of blood;
5.
Decrease in the viscosity of blood.

It should be emphasized that the above effects are not exerted separately, but conjointly they result in the enhancement of blood flow.

LMD, used in the treatment of shock, produces significant increases in blood volume, central venous pressure, cardiac output, stroke volume, blood pressure and urinary output. It reduces blood viscosity, peripheral resistance and improves peripheral blood flow with the release of sequestered blood cells, thereby increasing venous return to the heart.

When used as part of the pump prime for extracorporeal procedures, LMD, as compared to whole blood, albumin 5%, or whole blood plus 5% dextrose and water, leads to less destruction of red blood cells and platelets, reduces intravascular hemagglutination and maintains erythrocyte electronegativity.

The infusion of LMD (dextran 40) during and after surgical trauma reduces the incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients subject to surgical procedures with a high incidence of thromboembolic complication. Unlike antithrombogenic agents of the anticoagulant type, LMD does not achieve its effect so much by blocking fibrinogen-fibrin conversion but acts by simultaneously inhibiting other mechanisms essential to thrombus formation such as vascular stasis and platelet adhesiveness and by altering the structure and thereby the lysability of fibrin clots.

Histopathological studies have shown that the development of a mural platelet thrombus is the first stage of thrombus formation not only in the arterial, but also in the venous system. A number of studies have further shown that many patients who develop thromboembolic complications show an abnormally high platelet adhesiveness. Infusion of LMD has been shown to reduce platelet adhesiveness as measured by various in vitro tests on blood samples obtained from humans and to inhibit the growth of a mural platelet thrombus at the site of experimental (laser beam) injury in the rabbit's ear chamber.

Studies have shown an increase in the lysability of thrombi formed in the presence of dextran. A consistent and characteristic alteration in fibrin structure has been observed when fibrin is formed in the presence of dextran, and further experiments demonstrated such fibrin to be more susceptible to plasmin digestion. Other studies have shown that dextran infused into patients during surgery increases the lysability of ex vivo thrombi. Controlled clinical trials have shown that thrombi in patients treated with dextran have a more pronounced tendency to undergo lysis as determined by phlebography.

LMD is evenly distributed in the vascular system. Its distribution according to molecular weight shifts toward higher molecular weights as the smaller molecules are excreted by the kidney. In normovolemic subjects, approximately 50% is excreted within 3 hours, 60% is excreted within 6 hours and about 75% within 24 hours. Reabsorption of dextran by the renal tubules is negligible. The unexcreted molecules of dextran diffuse into the extravascular compartment and are temporarily taken up by the reticuloendothelial system. Some of these molecules are returned to the intravascular compartment via the lymphatics. Dextran is slowly degraded by the enzyme dextranase to glucose.

Solutions containing carbohydrate in the form of dextrose restore blood glucose levels and provide calories. Carbohydrate in the form of dextrose may aid in minimizing liver glycogen depletion and exerts a protein sparing action. Dextrose injected parenterally undergoes oxidation to carbon dioxide and water.

Sodium chloride in water dissociates to provide sodium (Na+) and chloride (Cl-) ions. Sodium (Na+) is the principal cation of the extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl-) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in red blood cells. The distribution and excretion of sodium (Na+) and chloride (Cl-) are largely under the control of the kidney, which maintains a balance between intake and output.

Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production).

Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na+) plays a major role in maintaining physiologic equilibrium.

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Clinical Pharmacology

CLINICAL PHARMACOLOGY

The fundamental action of LMD (dextran 40) is the enhancement of blood flow, particularly in the microcirculation. This enhancement is due to:

1.
Its primary effect of volume expansion with resultant hemodilution;
2.
Maintenance of the electronegativity of red blood cells;
3.
Coating of red blood cells and platelets;
4.
Increase in the suspension stability of blood;
5.
Decrease in the viscosity of blood.

It should be emphasized that the above effects are not exerted separately, but conjointly they result in the enhancement of blood flow.

LMD, used in the treatment of shock, produces significant increases in blood volume, central venous pressure, cardiac output, stroke volume, blood pressure and urinary output. It reduces blood viscosity, peripheral resistance and improves peripheral blood flow with the release of sequestered blood cells, thereby increasing venous return to the heart.

When used as part of the pump prime for extracorporeal procedures, LMD, as compared to whole blood, albumin 5%, or whole blood plus 5% dextrose and water, leads to less destruction of red blood cells and platelets, reduces intravascular hemagglutination and maintains erythrocyte electronegativity.

The infusion of LMD (dextran 40) during and after surgical trauma reduces the incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients subject to surgical procedures with a high incidence of thromboembolic complication. Unlike antithrombogenic agents of the anticoagulant type, LMD does not achieve its effect so much by blocking fibrinogen-fibrin conversion but acts by simultaneously inhibiting other mechanisms essential to thrombus formation such as vascular stasis and platelet adhesiveness and by altering the structure and thereby the lysability of fibrin clots.

Histopathological studies have shown that the development of a mural platelet thrombus is the first stage of thrombus formation not only in the arterial, but also in the venous system. A number of studies have further shown that many patients who develop thromboembolic complications show an abnormally high platelet adhesiveness. Infusion of LMD has been shown to reduce platelet adhesiveness as measured by various in vitro tests on blood samples obtained from humans and to inhibit the growth of a mural platelet thrombus at the site of experimental (laser beam) injury in the rabbit's ear chamber.

Studies have shown an increase in the lysability of thrombi formed in the presence of dextran. A consistent and characteristic alteration in fibrin structure has been observed when fibrin is formed in the presence of dextran, and further experiments demonstrated such fibrin to be more susceptible to plasmin digestion. Other studies have shown that dextran infused into patients during surgery increases the lysability of ex vivo thrombi. Controlled clinical trials have shown that thrombi in patients treated with dextran have a more pronounced tendency to undergo lysis as determined by phlebography.

LMD is evenly distributed in the vascular system. Its distribution according to molecular weight shifts toward higher molecular weights as the smaller molecules are excreted by the kidney. In normovolemic subjects, approximately 50% is excreted within 3 hours, 60% is excreted within 6 hours and about 75% within 24 hours. Reabsorption of dextran by the renal tubules is negligible. The unexcreted molecules of dextran diffuse into the extravascular compartment and are temporarily taken up by the reticuloendothelial system. Some of these molecules are returned to the intravascular compartment via the lymphatics. Dextran is slowly degraded by the enzyme dextranase to glucose.

Solutions containing carbohydrate in the form of dextrose restore blood glucose levels and provide calories. Carbohydrate in the form of dextrose may aid in minimizing liver glycogen depletion and exerts a protein sparing action. Dextrose injected parenterally undergoes oxidation to carbon dioxide and water.

Sodium chloride in water dissociates to provide sodium (Na+) and chloride (Cl-) ions. Sodium (Na+) is the principal cation of the extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl-) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in red blood cells. The distribution and excretion of sodium (Na+) and chloride (Cl-) are largely under the control of the kidney, which maintains a balance between intake and output.

Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production).

Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na+) plays a major role in maintaining physiologic equilibrium.

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