Injectable contraception (IC) is used by more than 18 million women worldwide. The composition of the IR includes long-acting progestogens, devoid of estrogenic and androgenic activity:
Depot medroxyprogesterone acetate ("Tsepo-Provera")..
- norethisterone enanthate (“YET-EY”). Mechanism of contraceptive action of IR:
- suppression of ovulation (inhibitory effect on the hypothalamic-pituitary system),
Changes in the physicochemical properties of the mucus of the cervical canal (its viscosity and fibrousness increase), preventing the penetration of sperm,
Violation of the level of enzymes “responsible” for fertilization process,
Transformations in the endometrium that prevent implantation.
Contraceptive effectiveness of IR - 0.5-1.5 pregnancies per 100 women/years.
IR usage mode:
"Depo-provera-]50" - the first dose of the drug (150 mg/1 ampoule) is administered in the first 5 days menstrual cycle: subsequent injections are made every 12 weeks (3 months + 5 days);
"YAEG-EYA" - injections of the drug are performed once every 8 weeks (200 mg/1 ampoule).
Before administering IR, shake the bottle. The drug is injected deep into gluteal muscle. The injection area is not massaged. Fertility restoration occurs within 4-24 months after the last injection.
Indications:
- inability to take other drugs regularly on a daily basis
gee hormonal drugs if desired, increase the interval between births.
Late reproductive age (over 35 years),
Contraindications to the prescription of estrogens (a number of extragenital diseases or a history of estrogen-dependent complications),
Lactation period (6 weeks after birth),
Use as "post-abortion" contraception.
Contraindications:
Pregnancy
Pathological uterine bleeding of unknown origin,
Planning pregnancy in the near future (especially in patients aged 30 to 40 years),
Malignant diseases reproductive organs and systems (with the exception of endometrial cancer) and mammary glands,
NET-EN is not acceptable during lactation. Side effects:
- menstrual irregularities (especially in the first months of contraception),
Galactorrhea,
Dizziness, headache,
Fatigue,
Irritability,
Depression,
Weight gain.
Decreased libido. Limitations of the method:
- menstrual irregularities, especially in the first months of contraception (dysmenorrhea, acyclic uterine bleeding, oligomenorrhea, amenorrhea),
The need for regular injections.
Advantages of the method:
-
Simplicity and confidentiality of use,
Low frequency metabolic disorders(due to the absence of an estrogenic component),
Therapeutic effects for endometriosis. premenstrual and menopausal syndromes, dysfunctional uterine bleeding, algomenorrhea, hyper-polymenorrhea, hyperplastic processes in the endometrium, recurrent inflammatory diseases internal genital organs.
- within two weeks after the first injection of the drug, use additional contraception,
Injections of the drug should be carried out every 3 months (+5 days) medical institution,
If any complaints arise ( special attention deserve heavy uterine bleeding, headaches, depression, enlargement body weight, frequent urination) consult a doctor.
Stop administering the drug several months before the planned pregnancy (it must be taken into account that fertility after stopping injections of the drug is restored after 4-24 months),
In case of prolonged amenorrhea, consult a doctor to rule out pregnancy.
Monitoring patients using IR:
- examination and identification of complaints every 3 months,
In case of prolonged intermenstrual bleeding, it is necessary to exclude pregnancy, inflammatory processes of the genitals, organic diseases: after excluding the listed conditions, additionally prescribe ethinyl estradiol (0.05-0.1 mg daily) from 7 to 21 days of the cycle (but not more than 1-2 cycles) or estradiol ( 1
Zraza tablet/day) for three days; in the absence of a positive effect or heavy bleeding- administer 5 mg of estradiol cypionate: if necessary, repeat the drug after 24 hours; continued bleeding is an indication for hysteroscopy with therapeutic and diagnostic curettage of the endometrium.
4.4. Subcutaneous implants
Norplant S^ogr1apG) - manufacturer "Le1ga5 PHngta-seipsa15"\ Finland. It is presented in flexible silastic capsules with a length of 3.4 cm and a diameter of 2.5 mm, each of which contains 35 mg of levonorgestrel. Norplant-2 - consists of 2 capsules 44 mm long and 2.4 mm in diameter, containing 35 mg of levonorgestrel.
Mechanism of contraceptive action is based on the release of levonorgestrel by Norplant capsules at a constant rate (30 mcg/day), which provides the following effects:
Ovulation suppression
Character change cervical mucus, difficulty in sperm penetration,
Endometrial atrophy, preventing implantation,
Premature luteolysis.
Contraceptive effectiveness of Norplant - 0.5-H.5 pregnancies per 100 women/years.
Method of application. Before replanting the capsule, a detailed gynecological examination is performed. The capsules are implanted fan-shaped into the subcutaneous fatty tissue of the inner surface of the forearm through a 1 mm long skin incision using a special trocar. The procedure is performed under local anesthesia in compliance with the rules of asepsis. The capsules should be placed shallowly (after the wound has healed, they can be easily palpated through the skin) for more --^
easy removal. The contraceptive effectiveness of Nor-Plant lasts for 5 years. norplanta-2 - for 3 years.
Administration time:
- in the first 7 days of the menstrual cycle,
Immediately after an induced abortion,
6-8 weeks after birth (provided that the patient was not sexually active before or was protected using other methods of contraception).
Removal implants are carried out under local anesthesia: a) at the request of the patient at any time, b) according to indications, c) by the end of the 5th year of use.
Indications for use subcutaneous implants:
- late reproductive age,
The patient's desire to increase the interval between births,
A history of estrogen-dependent adverse reactions,
Extragenital diseases that prevent the use of combined estrogen-gestagen drugs,
Small uterine fibroids (up to 8 weeks),
Conditions in which gestagens have a therapeutic effect (fibrocystic mastopathy, hyperpolymenorrhea, algomenorrhea, ovulatory pain).
Contraindications:
- pregnancy,
Uterine bleeding unknown origin,
Malignant tumors reproductive system. Side effects and complications:
- menstrual irregularities (40-45%), mainly in the first 6-12 months (metrorrhagia, menorrhagia, oligomenorrhea, amenorrhea).
Inflammatory process in the area of capsule administration.
Galactorrhea.
Nausea,
Headache(5-20%), dizziness.
Acne (5-20%), hirsutism,
Increase in body weight,
Depression,
Education functional cysts ovaries,
Ectopic pregnancy (0.28 per 100 women/years, which is lower than the frequency of its development among women who do not protect themselves from pregnancy).
Limitations of the method:
- relative high cost of the drug,
Frequent menstrual irregularities. Advantages of the method:
- high contraceptive effect,
Possibility of use for extragenital diseases that exclude the use of combined estrogen-gestagen drugs,
Minor metabolic changes in carbohydrate and lipid metabolism, no adverse effects on the cardiovascular system,
Convenience associated with single use and continuous, prolonged action,
Eliminates the need to take the drug daily,
Reversibility,
Therapeutic effect for hyperpolymenorrhea, algomenorrhea. ovulatory pain, fibrocystic mastopathy
Reducing the risk of developing endometrial cancer. Recommendations for patients using subcutaneous implants:
- it should be taken into account that the maximum contraceptive effect of the drug begins 24 hours after administration of the capsule,
Do not wet the injection site until the skin incision is completely healed.
By the end of the 5th year, the capsules should be removed.
If the following complaints and symptoms appear, you should consult a doctor:
a) pain, swelling, hyperemia in the area of capsule administration.
b) absence of menstruation or heavy uterine bleeding (to exclude pregnancy or organic pathology),
c) pain localized in lower parts abdomen (to exclude ectopic pregnancy or complicated functional ovarian cysts - rupture, torsion of the “leg” of the cyst),
d) capsule expulsion,
e) migraine-like headaches, blurred vision.
Gynecology - PopMed - 2005
Mechanism of contraceptive action of IR:
IR usage mode:
"Depo-provera-.150"- the first dose of the drug (150 mg/1 ampoule) is administered in the first 5 days of the menstrual cycle: subsequent injections are made every 12 weeks (3 months + 5 days);
"NET-EN"- injections of the drug are performed once every 8 weeks (200 mg/1 ampoule).
Before administering IR, shake the bottle. The drug is injected deep into the gluteal muscle. The injection area is not massaged. Fertility restoration occurs within 4-24 months after the last injection.
Indications: o the inability to regularly take other hormonal medications on a daily basis if you want to increase the interval between births.Side effects:
Limitations of the method:
Advantages of the method:
Insulins long acting are able to maintain normal blood glucose levels throughout the day for any degree of diabetic condition. At the same time, a decrease in the concentration of sugar in plasma occurs due to its active absorption by body tissues, in particular the liver and muscles. The term “long” insulin makes it clear that the duration of the effect of such injections, compared to other types of glucose-lowering drugs, is longer.
Long-acting insulin is available in the form of a solution or suspension for intravenous and intramuscular injection. U healthy person this hormone is continuously produced by the pancreas. A long-acting hormonal formulation was developed to mimic a similar process in people with diabetes. But extended-type injections are contraindicated for patients staying in diabetic coma or precomatose state.
At the moment, long-term and ultra-long-term products are common:
Hormonal substance | Peculiarities | Release form |
Humulin NPH | Activates after 60 minutes, maximum effect achieved in 2-8 hours. Regulates blood glucose levels for 18-20 hours. | Suspension of extended type for subcutaneous administration. Sold in bottles of 4-10 ml or cartridges of 1.5-3.0 ml for syringe pens. |
Protafan NM | It starts working within 1-1.5 hours. Maximum effectiveness appears after 4-12 hours and lasts at least a day. | Suspension for s.c. administration. Packaged in 3 ml cartridges, 5 pcs per package. |
Insuman Bazal | Activates after 1-1.5 hours. Effective for 11-24 hours, the maximum effect occurs within 4-12 hours. | Extended insulin for subcutaneous administration. Available in 3 ml cartridges, 5 ml bottles and 3 ml cartridges for pen syringes. |
Gensulin N | Long-acting insulin is activated within 1.5 hours. The peak of activity occurs between 3-10 hours. The average period of action is a day. | Means for subcutaneous application. Sold in cartridges for syringe pens of 3 ml, in bottles of 10 ml. |
It begins to act 60 minutes after the injection, regulates the concentration of sugar in the blood for at least a day. | Cartridges are regular and for syringe pens, 3 ml, in bottles of 10 ml for subcutaneous use. |
|
Levemir FlexPen | Peak activity occurs after 3-4 hours. The duration of the effect of the prolonged agent is one day. | Extended-release insulin is sold in 3 ml syringe pens. |
The name of the glucose-lowering substance and how to use extended-release insulin can only be recommended by the attending physician.
In addition, people suffering from diabetes should not independently replace the long-acting drug with its analogue. Extended-type hormonal substances should be prescribed reasonably with medical point vision, and treatment with its help should be carried out only under the strict supervision of a physician.
Long-acting insulin, depending on the type of diabetes, can be combined with fast-acting remedy, which is done with the aim of performing its basal function, or used as a single drug. For example, in the first form of diabetes mellitus, long-acting insulin is usually combined with a short-acting or ultra-short-acting drug. In the second form of diabetes, medications are used separately. The list of oral hypoglycemic compounds with which a hormonal substance is usually combined includes:
Long-acting insulin can be taken as a single drug, as with other medications
As a rule, a long-acting glucose-lowering composition is used to replace drugs with an average duration of action. Due to the fact that to achieve the basal effect, the medium insulin composition is administered twice a day, and the long insulin composition is administered once a day, changing therapy in the first week can trigger the occurrence of morning or night hypoglycemia. The situation can be corrected by reducing the amount of the long-acting drug by 30%, which allows you to partially compensate for the lack of long-acting hormone by using short-acting insulin with meals. After which the dosage of the extended insulin substance is adjusted.
The basal composition is administered once or twice a day. After entering the body through injection, the hormone begins to show its activity only after several hours. At the same time, the time frame of action for each long-acting glucose-lowering substance listed in the table is different. But if you need to administer extended-release insulin in an amount exceeding 0.6 U per 1 kg of a person’s weight, then the specified dose is divided into 2-3 injections. At the same time, in order to exclude the occurrence of complications, injections are given in different parts of the body.
Let's look at how to avoid the side effects of insulin therapy.
Any insulin drug, regardless of the duration of its effect, can cause side effects:
More chances to prevent complications when diabetes mellitus Types 1 and 2 provide long-acting insulin. In addition, long-acting insulin makes diabetes treatment more convenient. To exclude the manifestation of these side effects, a diabetic must follow the diet prescribed by the doctor every day and constantly change injection sites.
Recently on pharmaceutical market There are two new FDA-approved long-acting medications available to treat diabetes in adults:
Tresiba is a new drug that is approved by the FDA
Long-acting insulin Degludec is intended for subcutaneous administration. The duration of regulation of blood glucose levels with its help is about 40 hours. Used to treat diabetics with the first and second forms of the disease. To prove the safety and effectiveness of the new extended-release drug, a series of studies were conducted in which more than 2,000 adult patients took part. Degludec has been used as an adjunct to oral treatment.
Today, the use of the drug Degludec is approved in the EU countries, Canada and the USA. A new development has appeared on the domestic market under the name Tresiba. The composition is sold in two concentrations: 100 and 200 U/ml, in the form of a syringe pen. Now you can normalize blood sugar levels with the help of a long-acting super remedy by using an insulin solution only three times a week.
Let us describe the drug Ryzodeg. The long-acting drug Ryzodeg is a combination of hormonal substances, the names of which are well known to diabetics - basal insulin Degludec and fast-acting Aspart (ratio 70:30). Two insulin-like substances interact specifically with endogenous insulin receptors, due to which they realize their own pharmacological effect similar to the effect of human insulin.
Safety and effectiveness of the newly developed drug long-term exposure have been proven clinical trial, which involved 360 adult diabetics.
Ryzodeg was taken in combination with another antihyperglycemic agent with food. As a result, a reduction in blood sugar was achieved to a level that had previously been achieved only with the use of established long-acting insulin preparations.
Long-acting hormonal medications Tresiba and Ryzodeg are contraindicated in people with acute complication SD. In addition, these medications, like the analogues discussed above, should be prescribed only by the attending physician, otherwise side effects in the form of hypoglycemia and various allergies cannot be avoided.
Tablets are of particular interest among prolonged dosage forms.
Extended-release tablets (synonyms - tablets with prolonged action, tablets with prolonged release) are tablets from which the drug substance is released slowly and evenly or in several portions. These tablets allow you to provide a therapeutically effective concentration of medicinal substances in the body for long period time.
The main advantages of these dosage forms are:
The following requirements apply to extended dosage forms:
The most physiologically indifferent method is prolongation by slowing down the absorption of drugs. Depending on the route of administration, prolonged forms are divided into dosage forms retard and depot dosage forms. Taking into account the kinetics of the process, dosage forms with periodic release, continuous and delayed release are distinguished. Depot dosage forms (from the French depot - warehouse, put aside. Synonyms - deposited dosage forms) are prolonged dosage forms for injections and implantations, ensuring the creation of a supply of the drug in the body and its subsequent slow release.
Depot dosage forms always fall into the same environment, in which they accumulate, in contrast to the changing environment of the gastrointestinal tract. The advantage is that they can be administered at longer intervals (sometimes up to a week).
In these dosage forms, slowing down absorption is usually achieved by using poorly soluble compounds of medicinal substances (salts, esters, complex compounds), chemical modification - for example, microcrystallization, placing medicinal substances in a viscous medium (oil, wax, gelatin or synthetic medium), using delivery systems - microspheres, microcapsules, liposomes.
The modern nomenclature of depot dosage forms includes:
Injection forms - oil solution, depot suspension, oil suspension, microcrystalline suspension, micronized oil suspension, insulin suspensions, microcapsules for injection.
Implantation forms - depot tablets, subcutaneous tablets, subcutaneous capsules (depot capsules), intraocular films, ophthalmic and intrauterine therapeutic systems. To designate parenteral application and inhalation dosage forms, the term “extended release” or more generally “modified release” is used.
Dosage forms retard (from Latin retardo - slow down, tardus - quiet, slow; synonyms - retardets, retarded dosage forms) are prolonged dosage forms that provide a supply of medicinal substance and its subsequent slow release. These dosage forms are used primarily orally, but are sometimes used for rectal administration.
To obtain dosage forms of retard, physical and chemical methods are used.
Physical methods include coating methods for crystalline particles, granules, tablets, capsules; mixing medicinal substances with substances that slow down absorption, biotransformation and excretion; use of insoluble bases (matrices), etc.
The main chemical methods are adsorption on ion exchangers and the formation of complexes. Substances bound to the ion exchange resin become insoluble and their release from dosage forms in digestive tract based solely on ion exchange. The rate of release of the drug substance varies depending on the degree of grinding of the ion exchanger and the number of its branched chains.
Depending on the production technology, there are two main types of retard dosage forms - reservoir and matrix.
Reservoir-type forms are a core containing the drug substance and a polymer (membrane) shell, which determines the release rate. The reservoir can be a single dosage form (tablet, capsule) or a dosage microform, many of which form the final form (pellets, microcapsules).
Matrix-type retard forms contain a polymer matrix in which the medicinal substance is distributed and very often takes the form of a simple tablet. Dosage forms of retard include enteric granules, retard dragees, enteric-coated dragees, retard and retard forte capsules, enteric-coated capsules, retard solution, rapid retard solution, retard suspension, two-layer tablets, enteric tablets, frame tablets, multilayer tablets, tablets retard, rapid retard, retard forte, retard mite and ultraretard, multiphase coated tablets, film coated tablets, etc.
Taking into account the kinetics of the process, dosage forms are distinguished with periodic release, continuous release and delayed release.
Intermittent-release dosage forms (synonym: intermittent-release dosage forms) are long-acting dosage forms that, when administered into the body, release the drug substance in portions that essentially resemble the plasmatic concentrations created by normal dosing every four hours. They provide repeated action medicine.
In these dosage forms, one dose is separated from another by a barrier layer, which can be film, pressed or coated. Depending on its composition, the dose of the drug can be released either after a given time, regardless of the localization of the drug in the gastrointestinal tract, or at a certain time in the required part of the digestive tract.
Thus, when using acid-resistant coatings, one part of the drug substance can be released in the stomach, and the other in the intestines. At the same time, the period general action The duration of the drug can be extended depending on the number of doses of the medicinal substance contained in it, that is, on the number of layers of the tablet. Periodic release dosage forms include bilayer tablets and multilayer tablets.
Sustained release dosage forms are prolonged dosage forms that, when administered into the body, release an initial dose of the drug substance, and the remaining (maintenance) doses are released at a constant rate that matches the rate of elimination and ensures the constancy of the desired therapeutic concentration. Dosage forms with continuous, uniformly extended release provide the maintenance effect of the drug. They are more effective than periodic release forms, as they provide a constant concentration of the drug in the body at a therapeutic level without pronounced extremes, and do not overload the body with excessively high concentrations.
Continuous-release dosage forms include frame tablets, microform tablets and capsules, and others.
Delayed-release dosage forms are long-acting dosage forms that, when administered into the body, release the drug substance starting later and lasting longer than from a regular dosage form. They provide a delayed onset of action of the drug. An example of these forms are suspensions ultralong, ultralente with insulin.
The range of extended-release tablets includes the following tablets:
Implantable tablets (syn. - implantablets, depot tablets, tablets for implantation) are sterile trituration tablets with prolonged release of highly purified medicinal substances for administration under the skin. It has the shape of a very small disk or cylinder. These tablets are made without fillers. This dosage form is very common for administration. steroid hormones. IN foreign literature the term "pellets" is also used. Examples - Disulfiram, Doltard, Esperal.
Retard tablets are oral tablets with prolonged (mostly intermittent) release of drugs. Usually they are microgranules of a medicinal substance surrounded by a biopolymer matrix (base). They dissolve layer by layer, releasing the next portion of the medicinal substance. They are obtained by pressing microcapsules with hard core on tablet machines. Soft fats are used as excipients, which can prevent the destruction of the microcapsule shell during the pressing process.
There are also retard tablets with other release mechanisms - delayed, continuous and uniformly extended release. Varieties of retard tablets are “duplex” tablets and structural tablets. These include Potassium-normine, Ketonal, Cordaflex, Tramal Pretard.
Repetabs are multilayer coated tablets that ensure repeated action of the drug substance. They consist of an outer layer of drug substance, which is designed for rapid release, inner shell with limited permeability and a core that contains another dose of the drug.
Multilayer (layered) tablets make it possible to combine medicinal substances that are incompatible physical and chemical properties, prolong the effect of drugs, regulate the sequence of absorption of drugs at certain periods of time. The popularity of multilayer tablets is increasing as equipment improves and experience in their preparation and use accumulates.
Frame tablets (syn. Durules, durules tablets, matrix tablets, porous tablets, skeletal tablets, tablets with an insoluble frame) are tablets with a continuous, uniformly extended release and supporting effect of medicinal substances
To obtain them, excipients are used that form a network structure (matrix) in which the medicinal substance is included. Such a tablet resembles a sponge, the pores of which are filled with a soluble substance (a mixture of a medicinal substance with a soluble filler - sugar, lactose, polyethylene oxide, etc.).
These tablets do not disintegrate in the gastrointestinal tract. Depending on the nature of the matrix, they can swell and slowly dissolve or maintain their geometric shape throughout the entire period of stay in the body and be excreted in the form of a porous mass, the pores of which are filled with liquid. Thus, the drug substance is released by leaching.
Dosage forms can be multilayer. It is important that the medicinal substance is located predominantly in the middle layer. Its dissolution begins from the side surface of the tablet, while from the top and bottom surfaces At first, only the auxiliary substances from the middle layer diffuse through the capillaries formed in the outer layers. Currently, the technology for producing frame tablets using solid dispersed systems (Kinidin Durules) is promising.
The rate of drug release is determined by factors such as the nature of the excipients and the solubility of the drugs, the ratio of drugs and matrix-forming substances, the porosity of the tablet and the method of its preparation. Auxiliary substances for the formation of matrices are divided into hydrophilic, hydrophobic, inert and inorganic.
Hydrophilic matrices - from swelling polymers (hydrocolloids): hydroxypropylC, hydroxypropylmethylC, hydroxyethylmethylC, methyl methacrylate, etc.
Hydrophobic matrices - (lipid) - from natural waxes or from synthetic mono, di - and triglycerides, hydrogenated vegetable oils, higher fatty alcohols, etc.
Inert matrices are made from insoluble polymers: ethylC, polyethylene, polymethyl methacrylate, etc. To create channels in the water-insoluble polymer layer, water-soluble substances (PEG, PVP, lactose, pectin, etc.) are added. By being washed out of the tablet frame, they create conditions for the gradual release of drug molecules.
To obtain inorganic matrices, non-toxic insoluble substances are used: Ca2HPO4, CaSO4, BaSO4, aerosil, etc.
Speystabs are tablets with a medicinal substance included in a solid fat matrix, which does not disintegrate, but is slowly dispersed from the surface.
Lontabs are extended-release tablets. The core of these tablets is a mixture of medicinal substances with high molecular weight waxes. They do not disintegrate in the gastrointestinal tract, but slowly dissolve from the surface.
One of modern methods Prolonging the action of tablets is to coat them with coatings, in particular Aqua Polish coatings. These coatings provide prolonged release of the substance. They have alkaliphilic properties, thanks to which the tablet is able to pass through the acidic environment of the stomach unchanged. Solubilization of the coating and release of active substances occurs in the intestine. The release time of the substance can be controlled by adjusting the viscosity of the coating. It is also possible to set the release time of various substances in combination preparations.
Examples of the compositions of these coatings:
Another coating option replaces sodium carboxymethylcellulose with polyethylene glycol.
Of great interest are tablets whose prolonged action is determined by the matrix or filler. Sustained release of the drug from such tablets is achieved by using an injection molding technique in which the drug is embedded in a matrix, for example using cationic or anionic plastics as the matrix.
The initial dose is soluble in gastric juice thermoplastic from epoxy resin, and the delayed dose - into a copolymer insoluble in gastric juice. In the case of using an inert, insoluble matrix (for example, polyethylene), the release of the drug from it occurs by diffusion. Biodegradable copolymers are used: wax, ion exchange resins; The original matrix preparation is a system consisting of a compact material that is not absorbed by the body, in which there are cavities connected to the surface by channels. The diameter of the channels is at least two times smaller than the diameter of the polymer molecule in which the active substance is located.
Tablets with ion exchangers - prolongation of the action of a medicinal substance is possible by increasing its molecule due to precipitation on an ion exchange resin. Substances bound to the ion exchange resin become insoluble, and the release of the drug in the digestive tract is based only on the exchange of ions.
The rate of release of the drug substance varies depending on the degree of grinding of the ion exchanger (grains with a size of 300-400 microns are more often used), as well as on the number of its branched chains. Substances that give an acidic reaction (anionic), for example, derivatives of barbiturate acid, are associated with anion exchangers, and in tablets with alkaloids (ephedrine hydrochloride, atropine sulfate, reserpine, etc.) cation exchangers (substances with an alkaline reaction) are used. Tablets with ion exchangers maintain the level of action of the medicinal substance for 12 hours.
Some foreign companies are currently developing so-called “drilled” tablets with prolonged action. Such tablets are formed with one or two planes on its surface and contain a water-soluble ingredient. "Drilling" planes in the tablets creates an additional interface between the tablets and the medium. This, in turn, determines a constant rate of release of the drug, since as the active substance dissolves, the release rate decreases in proportion to the decrease in the surface area of the tablet. Creating these holes and enlarging them as the tablet dissolves compensates for the decrease in tablet area as it dissolves and keeps the dissolution rate constant. Such a tablet is coated with a substance that does not dissolve in water, but allows it to pass through.
As the tablets move through the gastrointestinal tract, the absorption of the drug substance decreases, therefore, in order to achieve a constant rate of entry of the substance into the body for drugs that undergo resorption throughout the gastrointestinal tract, the rate of release of the drug substance must be increased. This can be achieved by varying the depth and diameter of the "drilled" tablets, as well as changing their shape.
Long-acting tablets have been created, based on the principle of hydrodynamic balance, the effect of which is manifested in the stomach. These tablets are hydrodynamically balanced so that they are buoyant in gastric juice and retain this property until the drug substance is completely released from them. For example, tablets are produced abroad that reduce the acidity of gastric juice. These tablets are two-layer, and hydrodynamically balanced in such a way that upon contact with gastric juice, the second layer acquires and maintains such a density that it floats in the gastric juice and remains there until all anti-acid compounds are completely released from the tablet.
One of the main methods for obtaining matrix carriers for tablets is pressing. In this case, a variety of polymeric materials are used as matrix materials, which over time decompose in the body into monomers, that is, almost completely decompose.
Thus, at present, in our country and abroad, they are developing and producing various types solid dosage forms of prolonged action from more simple tablets, granules, dragees, spansuls to more complex implantable tablets, tablets of the "Oros" system, therapeutic systems with self-regulation. It should be noted that the development of long-acting dosage forms is associated with the widespread use of new excipients, including polymer compounds.
New opportunities for helping people with schizophrenia are being opened up by long-acting antipsychotic drugs. These are ampoule forms of antipsychotics for intramuscular injection.
Injecting a neuroleptic into a muscle, dissolved in oil (for example, olive), allows one to achieve its long-term stable concentration in the blood. Being absorbed into the blood gradually, the drug exerts its effect within 2–4 weeks.
Medium (minor) neuroleptics include drugs with moderate antipsychotic and sedative properties that do not cause significant side effects. Polyvalent antipsychotics combine a powerful antipsychotic effect with a sedative or disinhibiting effect. The group of disinhibiting neuroleptics has an activating effect mainly when administered in small doses.
The use of long-acting forms of antipsychotics greatly facilitates long-term outpatient therapy. The delayed, or retarded, effect of these compounds is associated with various mechanisms. When the active molecule combines with carboxylic acids, esters are formed, which, due to delayed hydrolysis, gradually release the active substance from the depot. The duration of action of the drug is determined by the type of carboxylic acid. Thus, when combined with enanthanic acid, the complete release of the neuroleptic occurs within a day, with uncylenic acid within 15-21 days, with decanoic acid in 16-25 days, and with palmitic acid in 25-28 days. Less frequent administration of such a neuroleptic leads to an exacerbation of productive symptoms, and with more frequent administration, cumulation is possible.
Long-acting antipsychotic medications have a number of undeniable advantages over regular ones. They make it possible to ensure maximum continuity of therapeutic effects, reliable control over the use of antipsychotics in the event that the patient does not have a proper understanding of the need for long-term therapy; a more stable and lower concentration of antipsychotic in the blood, which is probably associated with less severity side effects; lower total dose, which also reduces the risk of late side effects.
By now there is enough significant number long-acting forms of antipsychotics, and exclusively classical (traditional): fluphenazine decanoate (moditen-depot, lioridin-depot); , flupentixol decanoate (fluanxol-depot), zuclopenthixol decanoate (clopixol-depot), zuclopenthixol acetate (clopixol-acufaz), haloperidol decanoate. Unfortunately, Piportil L4 is now practically not used in Russia, which further narrows the palette of long-acting products used.
ASSESSMENT OF ADVANTAGES AND DISADVANTAGES OF LONG-LONGING NEUROLEPTICS:
Possibility of controlled treatment in non-compliant patients
More stable concentration of antipsychotic in the blood, which ensures increased effectiveness of maintenance, anti-relapse therapy
Lower costs for patients and their families
A more convenient drug regimen for working patients, which has important psychotherapeutic significance
Better tolerability of neuroleptic therapy in patients with gastrointestinal pathology
Possibility of using a lower dose of correctors
Absence of withdrawal syndrome when patients spontaneously stop treatment
There is no need for relatives to monitor the patient, which creates a softer psychotherapeutic atmosphere in the family
Most traditional antipsychotics require the use of correctors, which largely eliminates the convenience of rare injections of the drug (long-lasting forms of correctors are still unknown)
Possibility of disability of patients with long-term use traditional long-acting antipsychotics.
Narrow spectrum of action (traditional prolongs do not affect negative symptoms).
The impossibility of quickly relieving pronounced side effects if patients are intolerant to prolongation.
Difficulty of calculation daily dose when switching from the tablet form of an antipsychotic. Despite the presence of the so-called replacement rates, the issue of achieving an equivalent dose most often has to be decided individually.
The impossibility of maneuvering both dosages and combinations of drugs, which especially complicates the treatment of patients with rapid dynamics of symptoms during an attack, as well as patients with a tendency to develop postpsychotic depression.
Limited choice of antipsychotic, because not all of them have prolonged forms
There is currently no new generation of long-acting antipsychotics in Russia
The absence of all long-acting drugs in the lists of free drugs, except moditene depot, which makes it impossible for some patients to use these drugs
The need for a long wait (several weeks if prolongation is ineffective) to avoid polypharmacy and intensification adverse events during the interaction of drugs of different chemical groups
The need for careful monitoring of the time of the last injections of the drug, because Depending on the dynamics of symptoms, the frequency of administration of prolong may be different.
Unfortunately, to date there have been isolated observations comparative effectiveness and the safety of the above long-acting antipsychotics. At the same time, statistical data on the frequency of use cannot be considered a criterion for the quality of the drug, because for material reasons, cheaper ones or those included in the list are used free medicines. All this encourages us to have a broad discussion about the use of this category of drugs in clinical practice.
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Biopsychosocial model of schizophrenia
At present, the most productive approach to considering such mental illness Like schizophrenia, the biopsychosocial model is accepted by most professionals around the world. "Bio" means in development of this disease An important role is played by the biological characteristics of the body - the functioning of brain systems and metabolism in it. These biological features predetermine the next component - some features of the psyche both during its development in childhood and functioning in adulthood.
The system of neurons, the exchange of information between which occurs thanks to the dopamine molecule, is called the dopamine neurotransmitter system. Dopamine is released at the right time from nerve ending one cell and, once in the space between two cells, finds special areas (so-called dopamine receptors) on the process of another - neighboring cell, to which it attaches. In this way, information is transferred from one brain cell to another.
There are several subsystems in the dopamine system of the brain. One is responsible for the functioning of the cerebral cortex, the other, extrapyramidal, for muscle tone, and the third for the production of hormones in the pituitary gland.
Features of the dopamine neurotransmitter system are the most important biological prerequisite for the disease of schizophrenia
“Psycho” indicates the psychological characteristics of a person that make him more vulnerable than others to the effects of various stressors (circumstances that cause a state of stress in a person, i.e. a physiological and psychological reaction of adaptation, or a reaction of maintaining balance). Such a greater vulnerability than others means that even those circumstances that other people can overcome painlessly can cause a painful reaction in these highly vulnerable people. Such a reaction may result in the development of psychosis. They talk about individually reduced stress resistance of these people, i.e. decreased ability to respond to stress without developing a disease state.
People predisposed to developing schizophrenia have reduced resistance to stress
Examples are well known from practice when such events as moving from class to class, from school to school, infatuation with a classmate or classmate, graduation from school or college, i.e. events that are frequent in the lives of most people become “triggers” in the development of schizophrenia in people predisposed to this disease. We are talking here about the role in the development of the disease of social factors that a person encounters when interacting with other people. An indication of the role of social circumstances that become stressful for vulnerable people is contained in the term “biopsychosocial” component of the model.
From the above, it becomes obvious that help for people suffering from schizophrenia should consist of attempts to influence all three components involved in the development of the disease and, very importantly, supporting this disease.
In modern psychiatry, assistance to people suffering from schizophrenia consists of: 1) drug treatment(with the help of medications), which is aimed at normalizing the functioning of the dopamine system nerve cells brain and, as a consequence, increase stress resistance; 2) psychological treatment, i.e. psychotherapy aimed at correcting those psychological characteristics that contributed to the development of the disease, psychotherapy aimed at developing the ability to cope with the symptoms of the disease, as well as psychotherapy aimed at creating obstacles psychological consequences illness, such as withdrawal from other people; 3) social measures aimed at maintaining a person’s functioning in society - support in maintaining the patient’s professional status, social activity, training his social interaction skills, taking into account social requirements and norms, as well as measures that would help normalize interaction with loved ones. The last component involves not only helping the patient himself, but also working with the social environment, in particular with family members, who, not least of all, need help and support.
In addition to antipsychotic, neuroleptics also have a number of other effects:
· calming (sedative), which allows the use of antipsychotics to reduce internal tension, attacks of agitation and even aggression;
· sleeping pills, with an important advantage of antipsychotics as sleeping pills is that, unlike tranquilizers, they do not cause complications such as the formation of mental and physical dependence, and after normalization of sleep they can be canceled without any consequences;
· activating, i.e. the ability of some antipsychotics to reduce inactivity;
normothymic (stabilizing mood), especially characteristic of the so-called atypical antipsychotics (see below), which, due to the presence this effect can be used to prevent the next attack of schizophrenia or schizoaffective psychosis or reduce its severity;
· “behaviour-correcting” effect – the ability of some antipsychotics to smooth out behavioral disorders (for example, painful conflict, the desire to run away from home, etc.) and normalize desires (food, sexual);
· antidepressant, i.e. ability to improve mood;
· antimanic – the ability to normalize pathologically elevated, elevated mood;
· improvement of cognitive (cognitive) mental functions– the ability to normalize the thinking process, increase its consistency and productivity;
vegetostabilizing (stabilization vegetative functions– sweating, heart rate, level blood pressure etc.).
These effects are associated with the influence of antipsychotics not only on dopamine, but also on other systems of nerve cells in the brain, in particular on the norepinephrine and serotonin systems, in which the transmitter of information between cells is norepinephrine or serotonin, respectively.
Table 1 presents the main effects of antipsychotics and lists drugs that have these properties.
Side effects are also associated with the effect of antipsychotics on the dopamine system of nerve cells in the brain, i.e. unwanted effects. This is an opportunity at the same time as providing antipsychotic action influence muscle tone or change some parameters of hormonal regulation (for example, the menstrual cycle).
When prescribing antipsychotics, their effect on muscle tone is always taken into account. These effects are undesirable (side effects). Because muscle tone is regulated by the extrapyramidal system of the brain, they are called extrapyramidal side effects. Unfortunately, most often the effect of neuroleptics on muscle tone cannot be avoided, but this effect can be corrected with the help of cyclodol (Parcopan), Akineton and a number of other drugs (for example, tranquilizers), which in this case are called correctors. To successfully select therapy, it is important to be able to recognize these side effects.
Main effects of antipsychotics
Classic or typical neuroleptics
Atypical antipsychotics and new generation drugs
Rispolept (speridan, risset)
Rispolept (speridan, risset)
Rispolept (speridan, risset)
Thioridazine (Sonapax) Clopixol
Rispolept (speridan, risset)
Improvement of cognitive functions
Rispolept (speridan, risset)
The effect of antipsychotics on muscle tone can manifest itself differently during the stages of therapy. So, in the first days or weeks of taking antipsychotics, the development of so-called muscular dystonia is possible. This is a spasm in one or another muscle group, most often in the muscles of the mouth, extraocular muscles or neck muscles. Spastic muscle contractions can be unpleasant, but can be easily eliminated with any corrector.
With longer use of antipsychotics, the development of symptoms of drug-induced parkinsonism is possible: tremors in the limbs (tremors), muscle stiffness, including stiffness of the facial muscles, stiff gait. When the initial symptoms of this side effect occur, the feeling in your legs ("cotton legs") may change. Opposite sensations may also appear: feelings of anxiety with a constant desire to change the position of the body, the need to move, walk, move your legs. Subjectively, the initial manifestations of this side effect are experienced as discomfort in the legs, a desire to stretch, a feeling of “ restless legs" This type of extrapyramidal side effect is called akathisia, or restlessness.
With many months, and often many years of taking antipsychotics, tardive dyskinesia may develop, which manifests itself involuntary movements in one or another muscle group (usually the muscles of the mouth). The origin and mechanism of this side effect is being actively studied. There is evidence that its development is facilitated by sudden changes in the regimen of taking antipsychotics - sudden breaks, withdrawal of drugs, which are accompanied by sharp fluctuations in the concentration of the drug in the blood. Table 2 shows the main manifestations of extrapyramidal side effects and tardive dyskinesia and measures to eliminate them.
The start of taking correctors to reduce the severity of extrapyramidal side effects may coincide with the time of prescription of the antipsychotic, but may also be delayed until such effects appear. The dose of the corrector required to prevent the development of extrapyramidal side effects is individual and selected empirically. Usually it ranges from 2 to 6 tablets of cyclodol or akinetone per day, but not more than 9 tablets per day. A further increase in their dose does not enhance the corrective effect, but is associated with the likelihood of side effects of the corrector itself (for example, dry mouth, constipation). Practice shows that not all people experience extrapyramidal side effects of antipsychotics and that not all cases require their correction during the course of treatment with antipsychotics. In approximately two-thirds of patients taking antipsychotics for more than 4-6 months, the dose of the corrector can be reduced (and in some cases even canceled), and no extrapyramidal side effects are observed. This is explained by the fact that with sufficiently long-term use of antipsychotics in the brain, compensatory mechanisms for maintaining muscle tone are activated and the need for correctors decreases or disappears.
Main neurological side effects of antipsychotic therapy and methods for their correction
(first days, weeks)
Spasm in the muscles of the mouth, eyes, neck
Cyclodol or Akineton 1–2 tablets. under the tongue
Any tranquilizer (phenazepam, nozepam, elenium, etc.) 1 table. under the tongue
Phenobarbital (or drops of Corvalol or Valocordin)
Caffeine (strong tea or coffee)
Ascorbic acid up to 1.0 g orally in solution
Piracetam 2-3 capsules orally
(first weeks, months)
Tremor, muscle stiffness, greasiness of skin
Cyclodol (Parcopan) or Akineton:
3-6 tables per day, but not more than 9 tablets.
up to 3 tables per day
(first weeks, months)
Restlessness, restlessness, desire to move, restless legs feeling
up to 30 mg per day
Tranquilizer (phenazepam, etc.)
up to 3 tables per day
(months and years from the start of taking medications)
Involuntary movements in certain muscle groups
Propranolol (anaprilin, obzidan) – in the absence of contraindications
up to 30 mg per day
Characteristics of new generation neuroleptics: new opportunities and limitations
It has been noted that when it is prescribed, characteristic extrapyramidal effects do not develop or are observed only in the most sensitive patients to the drug or when medium and high doses of the drug are prescribed. In addition, unusual components of the effect of this drug were noted - normothymic (i.e., the ability to stabilize mood), as well as improvement in cognitive functions (restoration of concentration, consistency of thinking). Subsequently, new antipsychotics were introduced into psychiatric practice, which received the stable name atypical, such as risperidone (Rispolept, Speridan, Risset), olanzanpine (Zyprexa), quetiapine (Seroquel), amisulpride (Solian), ziprasidone (Zeldox), Abilify. Indeed, when treated with the listed drugs, extrapyramidal side effects develop significantly less frequently compared to treatment with classical antipsychotics and only when high or medium doses are prescribed. This feature determines their significant advantage over classical (“typical” or “conventional”) neuroleptics.
In the process of studying the effectiveness of atypical antipsychotics, other distinctive features. In particular, the effectiveness of clozapine (leponex, azaleptin) in the treatment of resistant, i.e. conditions resistant to the action of classical neuroleptics. An important property of atypical antipsychotics is their ability to stabilize the emotional sphere, reducing mood swings both downward (in depression) and pathologically elevated (in manic states). This effect is called normothymic. Its presence allows the use of atypical antipsychotics, such as clozapine (azaleptin), rispolept and Seroquel, as drugs that prevent the development of another acute attack schizophrenia or schizoaffective psychosis. IN lately The ability of new generation antipsychotics to provide positive influence on cognitive (cognitive) functions in people suffering from schizophrenia. These drugs help restore consistency of thinking, improve concentration, resulting in increased intellectual productivity. Such characteristics of the new generation of antipsychotics, such as the ability to normalize the emotional sphere, activate patients, and have a positive effect on cognitive functions, explain the widespread opinion about their effect not only on productive (delusions, hallucinations, catatonic symptoms, etc.), but also on the so-called negative ( decreased emotional response, activity, impaired thinking) symptoms of the disease.
Recognizing the noted benefits of atypical antipsychotics, it should be noted that they, like any other drugs, cause side effects. In cases where they have to be prescribed in high doses, and sometimes even in medium doses, extrapyramidal side effects still appear and the advantage of atypical antipsychotics over classical ones in this regard decreases. In addition, these drugs may have a range of other side effects that resemble those of classical antipsychotics. In particular, the administration of rispolept can lead to a significant increase in the level of prolactin (a pituitary hormone that regulates the function of the sex glands), which is associated with the appearance of symptoms such as amenorrhea (cessation of menstruation) and lactorrhea in women and engorgement of the mammary glands in men. This side effect was noted during therapy with risperidone (Rispolept), olanzapine (Zyprexa), and ziprasidone (Zeldox). In some cases, when prescribing such atypical antipsychotics as olanzapine (Zyprexa), clozapine (Azaleptin), risperidone (Rispolept), an individual side effect is possible in the form of weight gain, sometimes significant. The latter circumstance limits the use of the drug, since exceeding a certain critical body weight is associated with the risk of developing diabetes mellitus.
The prescription of clozapine (azaleptin) involves regular monitoring of the blood picture with a study of the number of leukocytes and platelets, since in 1% of cases it causes inhibition of blood growth (agranulocytosis). Blood tests need to be done once a week for the first 3 months. taking the drug and once a month thereafter throughout the course of treatment. When using atypical antipsychotics, such side effects, such as swelling of the nasal mucosa, nosebleeds, low blood pressure, severe constipation, etc.
Long-acting neuroleptics
Currently, there is a fairly wide choice of long-acting antipsychotics. These are moditene-depot, haloperidol-decanoate, clopixol-depot (and clopixol prolong, but with a 3-day duration of action, clopixol-acufaz), fluanxol-depot, rispolept-consta.
Conducting antipsychotic therapy with long-acting drugs is convenient because the patient does not have to constantly remember the need to take them. Only some patients are forced to take correctors for extrapyramidal side effects. There are undoubted advantages of such antipsychotics in the treatment of patients who, upon withdrawal medicines or a decrease in the concentration of the drug in the blood required for them, they quickly lose understanding of the severity of their condition and they refuse treatment. Such situations often lead to a sharp exacerbation of the disease and hospitalization.
Noting the potential of long-acting antipsychotics, one cannot help but mention increased risk development of extrapyramidal side effects when using them. This is due, firstly, to the large amplitude of fluctuations in the concentration of the drug in the blood during the period between injections compared to taking tablet antipsychotics, and secondly, to the inability to “cancel” the drug already introduced into the body with individual hypersensitivity to its side effects in a particular patient. In the latter case, you have to wait until the prolongation drug is gradually, over several weeks, removed from the body. It is important to keep in mind that of the long-acting antipsychotics listed above, only Rispolept-Consta is classified as atypical.
Rules for antipsychotic therapy
It should be emphasized once again that the need for therapy with antipsychotics in people suffering from schizophrenia or schizoaffective psychosis is determined by the biological characteristics of the brain. According to modern biological data scientific research schizophrenia, these features are determined by the structure and functioning of the dopamine system of the brain and its excessive activity. This creates a biological basis for distortions in the selection and processing of information and, as a result, for the increased vulnerability of such people to stressful events. Neuroleptics that normalize the functioning of the dopamine system of nerve cells in the brain, i.e. influencing the basic biological mechanism of the disease, represent a means of pathogenetic treatment
A scientist who developed a theory of the characteristics of the dopamine neurotransmitter system of the brain in schizophrenia and gave an explanation of the biological mechanisms of the disease and therapeutic effect antipsychotics, – Arvid Carlsson was awarded the Nobel Prize
The prescription of antipsychotics is, of course, indicated in the active period of a continuous disease (without remissions), and there are reasons to set the patient up for long-term treatment with these drugs, at least over the next few years. Neuroleptics are also indicated for exacerbation of the disease in case of its paroxysmal course. In the latter situation, you need to keep in mind that average duration The period of exacerbation for schizophrenia is 18 months. All this time, the readiness of symptoms that “went away” under the influence of treatment remains ready to resume when the antipsychotic is discontinued. This means that even if the symptoms of the disease have disappeared after a month from the start of therapy, it should not be stopped. Research shows that by the end of the first year after stopping antipsychotics, 85% of people with schizophrenia experience a return of symptoms, i.e. an exacerbation of the disease occurs and, as a rule, there is a need for hospitalization. Premature cessation of neuroleptic therapy, especially after the first attack, worsens the overall prognosis of the disease, because An almost inevitable exacerbation of symptoms excludes the patient from social activity for a long time, assigning him the role of “sick,” contributing to his maladjustment. When remission occurs (significant weakening or complete disappearance of the symptoms of the disease), the dose of antipsychotics is gradually reduced to the level necessary to maintain a stable condition.
Maintenance therapy is not always perceived by patients and their relatives as necessary. Often, stability of well-being forms erroneous opinion that the long-awaited well-being has arrived and the disease will not recur, so why continue treatment?
Despite the achieved well-being, a person suffering from schizophrenia or schizoaffective psychosis retains the peculiarity of brain functioning in the form of excessive activity of the dopamine neurotransmitter system, as well as increased vulnerability to stressors and readiness to develop painful symptoms. Therefore, taking maintenance doses of an antipsychotic should be considered as replenishing the deficiency of a certain substance in the body, without which it cannot function at a healthy level.
Taking an antipsychotic in a maintenance dose, which can prevent exacerbation of psychosis and the need for hospitalization for many years, is not a treatment, but a way of life
To help the person suffering from schizophrenia to rethink the intake of maintenance doses of antipsychotics and other necessary medications, the help of specialists is required, which will be discussed in the next lecture. No less important, and sometimes paramount, is the understanding and support of his loved ones. Knowledge of the mechanisms of development of the disease and the essence of the assistance offered will help him gain greater confidence.
