Alprostadil

Pharmacological properties

Alprostadil is a synthetic analogue of prostaglandin e1 present in the human body under ordinary conditions. its effect is complex and is based on the promotion of microcirculation and the opening of collateral vessels. in the systemic and pulmonary circles of blood circulation, alprostadil causes vasodilation (at the level of arterioles and precapillary sphincters and / or also in the muscle arteries), relaxes the smooth muscles of the corpora cavernosa, and alprostadil maintains an open state of the arterial duct in the circulation circle of the fetus. affects blood coagulation, acting as an anti-adhesive and anti-aggregation agent on platelets. Alprostadil improves the rheological properties of blood by increasing the plasticity of red blood cells and reducing the aggregation ability of platelets. It has an anti-atherogenic effect by inhibiting the activation of neutrophils and excessive proliferation of vascular wall cells, as well as by decreasing the synthesis of CS and its adhesion to the walls of blood vessels. Alprostadil also has a fibrinolytic effect.

Pharmacokinetics Prostaglandin E1 (alprostadil) is an endogenous natural compound with a short T_½which is approximately 10 s. Alprostadil is metabolized in the lungs during the first passage - 60–90%. Due to enzymatic oxidation, 3 biologically active metabolites are formed: 15-keto-prostaglandin E1, 15-keto-13,14-dihydro-prostaglandin E1 and 13,14-dihydro-prostaglandin FG. Keto-metabolites have less biological activity than alprostadil, and the action of the metabolite 13,14-dihydro-prostaglandin FG is similar to the action of prostaglandin E1. It is important that prostaglandin FG lasts longer, T_½ is approximately 1 min (α-phase) and 30 min (β-phase). Probably, the pharmacodynamic effect of the drug is mainly caused by the action of this particular biologically active stable metabolite. The main metabolites are excreted in urine (up to 88%) and feces (12%).

Indications

Chronic obliterating diseases of the arteries of stages III and IV (according to the classification of fontaine).

Congenital heart defects in newborns associated with non-closure of the botallal duct (in order to temporarily ensure the functioning of the ductus arteriosus before corrective surgery).

Application

Adults

For intravenous therapy of chronic obliterating arterial diseases, the recommended dose is 50–200 μg, which is administered once a day or in two separate doses for at least 2-hour infusion of 200–500 ml of the drug solution.

As solvents use isotonic solution of sodium chloride (saline), 5% or 10% solution of glucose. Such a solution should be prepared immediately before the start of the infusion.

The course of treatment should last at least 2 weeks; in case of a positive effect, treatment should be carried out for another 7-14 days. However, the course of treatment should not exceed 4 weeks. If during the first 2 weeks of treatment the desired effect is not achieved, the drug should be discontinued.

Newborns

Alprostadil is preferably used as a continuous IV infusion (as an alternative, it is introduced into the arterial duct through the umbilical artery). The recommended initial dose is 0.01–0.05 mcg / kg / min; if there is a response to therapy, that is, signs of the opening or reopening of the botallal duct, the dose should be reduced to the minimum effective therapeutic dose (usually 0.01-0.02 μg / kg / min). In exceptional cases, if the initial dose is not effective, the dose of the drug can be increased to 0.1 μg / kg / min. Serious adverse reactions to the drug are a reason for dose reduction.

During the use of the drug, it is necessary to monitor the main vital signs, geodynamic parameters and acid-base balance (gases in the blood).

Recommendations for dilution of the concentrate for use in newborns

The contents of 1 ampoule of the drug Alprostan (0.2 ml) should be mixed with 9.8 ml of the appropriate solvent (for example, physiological solution, 5% or 10% glucose solution), which allows you to reach a concentration of 100 μg alprostadil in 10 ml r- pa The resulting solution in the future must be brought to a larger volume using the appropriate solution, which is suitable for use.

Contraindications

In chronic obliterating diseases of the arteries: hypersensitivity to alprostadil, pregnancy and lactation; acute and subacute period of myocardial infarction, severe or unstable angina pectoris; decompensated heart failure; severe heart rhythm disturbances; chronic bronchopulmonary obstructive diseases with respiratory failure; pulmonary edema, detection of infiltrative changes in the lungs during x-ray examination; acute or severe chronic liver failure; risk of developing hemorrhagic complications (stroke, stomach and / or duodenal ulcer, proliferative retinopathy with a tendency to bleeding, polytrauma).

Contraindications to the use of the drug in newborns include hypersensitivity to alprostadil, respiratory failure syndrome and spontaneous persistent opening of the ductus arteriosus.

Side effects

With different indications for use, various side effects are noted. if this drug is used to treat chronic obliterating diseases of the arteries, iv administration in most cases is complicated by inflammation of the veins proximal to the injection site (this is observed in almost 40% of patients). the appearance of a painful red ribbon on the skin along a given vein usually does not require immediate withdrawal of the drug; redness does not require any specific treatment and disappears within a few hours after the cessation of drug infusion or after changing the place of infusion. the incidence of such hyperemia increases depending on the dose and depends on the concentration of the drug or the rate of infusion. when using a central catheter, the incidence of such hyperemia decreases; however, a central catheter is not a prerequisite for drug treatment. the increase in infusion volume is primarily limited in patients with more severe heart failure (due to the risk of developing acute pulmonary edema or heart failure). Among less frequent adverse reactions, systemic symptoms (fatigue, dizziness, hyperhidrosis) or gastrointestinal disturbances (discomfort in the epigastric region, nausea, vomiting, diarrhea), headache, swelling of the extremities during which the infusion, arterial hypotension, orthostatic hypotension were reported , tachycardia, angina pectoris, fever and tremors, allergic reactions. infrequently reported pulmonary edema and heart failure. long-term treatment (≥4 weeks) can be complicated by reversible long bone hyperostosis. laboratory tests may indicate leukocytosis and leukopenia, occasionally an increase in srb titer.

When using the drug in newborns, the most common side effects included febrile conditions, diarrhea, arterial hypotension and vasodilation of the skin vessels, pulmonary hypoventilation, up to apnea, bradycardia or tachycardia, local skin reactions; less commonly - cramping, in exceptional cases, DIC. After using the drug for 7 weeks, painful changes in bone tissue (hyperostosis) were observed, characteristic exclusively for the lower extremities.

In 1% of newborns, the following adverse reactions to the drug were noted: shock, acute heart failure, hyperbilirubinemia, bleeding, lethargy, bradypnea, respiratory failure, tachypnea, anuria, impaired renal function, hypoglycemia, ventricular fibrillation, degree II AV block, supraventricular neck muscle tension, increased irritability, hypothermia, hypercapnia, hyperemia, hematuria, peritonitis, tachyphylaxis, hyperkalemia, thrombocytopenia and anemia.

Serious side effects are a reason for dose reduction.

special instructions

Special care is required in patients with severe or symptomatic arterial hypotension; in patients with heart failure (it is especially necessary to reduce the load on the circulatory system caused by the volume of solvent); in patients undergoing hemodialysis (treatment with alprostadil must be carried out only after hemodialysis is completed); in patients receiving anticoagulation therapy (due to the possibility of enhancing the effect of vasodilation). although the drug does not adversely affect compensated diabetes, caution should be exercised in elderly patients receiving insulin, especially in cases of severe vascular damage.

Infusion therapy is always part of the comprehensive treatment of patients with chronic obliterating diseases of the arteries. The clinical effect of such therapy is stable and persists even after a certain period of time (that is, after completion of the course of treatment).

Caution must be exercised in newborns, especially with bradypnea, arterial hypotension, tachycardia, and febrile conditions.

The ability to influence the speed of reactions when driving vehicles and working with other mechanisms. Unknown Possible systemic signs of arterial hypotension, dizziness or fatigue disappear shortly after the end of the infusion. It is caused by short biological T_½ active substance of the drug.

Interactions

Caution should be observed with the simultaneous administration of alprostadil with anticoagulants or antiplatelet agents due to the possible risk of bleeding.

The introduction of alprostadil enhances the action of antihypertensive drugs and vasodilators.

Incompatibility. Alprostadil in the form of a concentrate for infusion should not be diluted with any other solutions, except physiological, 5% or 10% glucose.

Overdose

In case of an overdose (decreased hell, flushing of the skin, general weakness), reduce the rate of infusion or cancel the drug. specific treatment is usually not required. with signs of depression of the respiratory center in newborns, IVL is performed.

Storage conditions

In a dry place protected from light and frost at a temperature of 1–5 ° C.

The drug must be used immediately after opening the ampoule. Otherwise, the user is responsible for the time and storage conditions after opening the ampoule prior to first use; this time should not exceed 24 hours at a temperature of 2–8 ° C.