Mechanisms of soaking (mechanisms for the transport of medicinal speeches) are presented in fig. 2.3.
The most common mechanism for the transport of medicinal speech is passive diffusion through the membranes of the intestinal wall clitin (enterocytes). The density of being wetted in this way is proportional to the gradient of the concentration of speeches and it is possible to lie down in the form of their diversity in the membrane (easier way of passive diffusion lipophilic non-polar speech ).
Mal. 2.3.
A - Diffusion; IN - filtration; W - Active transport; D - pinocytosis
Diffusion, ring out, give electricity to the undissociated become. The difference and degree of ionization of the medicinal process is determined by the pH in place of the intestinal duct. It is necessary to say that medicinal remedies with a path of passive diffusion are well soaked in the rectum, which is the basis for the introduction of medicinal remedies with a rectal path. See the passive transport presented in fig. 2.4.
Mal. 2.4.
Water, electrolytes and small hydrophilic molecules (for example, sechovin) are transported to the blood by another mechanism - filtration through pores in the intestinal epithelium. Filtration through the pores may be important for the absorption of medicinal products with a molecular weight of less than 100 So it depends on the concentration of the gradient.
Vikoristov specializes in the mechanisms of cellular membranes from vitreous energy for the transfer of song ions or molecules against the concentration of the gradient. Wines are characterized by vibrancy, saturation. p align="justify"> With active transport, there is a competition of speeches for a burning transport mechanism (for example, when certain vitamins and minerals are acquired). Stupin vmoktuvannya to lie down in the dose of the drug, oskіlki possibile the phenomenon of "number of proteins-carriers". Features of active transport are presented in fig. 2.5.
The main mechanism of smoking xenobiotics (Synthesizing medicinal speeches) - passive diffusion. For speeches of natural walking, such as amino acids, vitamins, essential microelements and others, in organisms there are specialized active transport mechanisms. And here the main path is conquered - active transport, and passive diffusion begins to play a role only for even higher concentrations.
The drug speech with great molecules or the complexes of the drug speech with the great transport molecule are wetted pinocytosis. In this case, there is an invasion of the membrane of the intestinal epithelium of the clitinum and the incorporation of a bulb (vacuole), filled with a suffocated motherland at once with faces. The vacuole migrates with the cytoplasm of the clitinum to the protylogenous side and swells into the inner middle of the organism. However, pinocytosis is not of significant importance for the treatment of medicinal products, and it is less likely to
in solitary depressions (for example, when acquired by the complex of cyanocobalamin with protein - the internal factor of Castle).
Mal. 2.5.
Modern technologies of kerovannoy vilnennya in the production of medicinal methods of vicory are such technological approaches as:
- vikoristannya additional speeches;
- granulation;
- microencapsulation;
- zastosuvannya special press;
- covered with casings, etc.
With their help, you can change the hour of disintegration of the tablet, the speed of disintegration, or the vision of medicinal speech, the place of vision, and the severity of the occurrence in the singal zone of the mucosal-intestinal tract (above the opening of the inoculation). I ce, with its blackness, signifies swidkist and fullness of soaking, the dynamics of the concentration of medicinal speech in the blood, tobto. bioavailability of the drug. For certain preparations, tablets are made with microparticles with adhesive dominance, which “stick” to the mucous membrane, or tablets that swell at the lining of the lining, that stinks float on the surface (otherwise) cannot pass through the pyloric sphincter in the intestines. On the rapidity of the disintegration of the tablets at the shunt, the method of their extraction is added. So, zvichayni (pressed) tablets are mіtsnіshі for trituration (molded). Shvidkіst disintegration lie down and in the form of additional speeches, which are victorious for the necessary powers of the tableted sum (thickness, plasticity, pressure, instead of water).
Intestinal tablets are covered with a shlyahka-resistant shell or granules or microcapsules, frontally covered with such shells. If necessary, the shells can be safe and keep the lock-up, at least for 1 year, which tablet should be carried out at the sluice. Obolonka can be finished with a tovstoy, for example, with blood, as sometimes it can have more weight, lower the core of the tablet, to avenge the medicinal speech. Thin fluffy shells (less than 10% per tablet mass) can be coated with cellulose, polyethylene glycols, gelatin, and gum arabic. With the selection of the shell and the introduction of additional speech, it is possible to increase the increase in the concentration of active speech in the blood, which is important for reducing the risk of the development of a negligible reaction, that (or) destroy the hour of reaching the maximum for a few years, so you need but continue this drug with the same time to speed up the frequency of taking it with the method compliance improvement. Prolonged tablets (retard), for example, have the ability to compress microgranules of medicinal speech in a biopolymer shell or seperate from a biopolymer matrix. With a step-by-step (ball-by-ball) scatter of the bases, the shells vibrate black portions of the liquor speech. Modern high-tech methods of delivery allow for step-by-step smooth wilting of medicinal speech, for example, for the opening of an osmotic vice in the middle of a capsule with a loose speech. Based on this principle, new pharmaceutical formulations of nifedipine (Korinfar Uno), indapamide (Indapamide retard-Teva), piribedil (Pronoran®), tamsulosin (Omnik Okas), glipizide (Glibenez retard), trazodone (Trittiko) ). Kerovane (controlled) vilification can be reached by victories in tablets of microcapsules with medicinal speech, coated with a special polymer. After the expansion of the spherical ball into the middle of the capsule, the motherland comes and the world separates the nucleus, the gradual development and diffusion of the medicinal speech through the membrane of the capsule. The main factor, the Viknitnie is the vicoristy of the subinths of Likkarsk forms, gets in the mind of the non-cereal vivilnnnya of the richest ebb for an hour of the passage of the main MISTSTSTENSTEVA LICKAYSHICE OF THE SHLUNKOVO-ChICK TRARTS-4-5 years old.
In the rest of the world, systems of nanoparticles are used for the delivery of drugs. Nanoparticles of lipids (liposomes) may have obvious advantages in connection with a high level of biointelligence and universality. Qi systems allow you to create pharmaceutical preparations for oral, oral, inhalation and parenteral routes of administration. The safety and efficacy of drugs based on liposomes have been reconsidered as potential candidates for pharmaceutical preparations, as well as vaccines, diagnostic tools, and nutraceuticals. The liposome of the clitin is shown in Fig. 2.6. Liposomes are similar to bulbs, they are composed of riches, decals, or less than one phospholipid bilayer. The polar nature of the nucleus allows polypshit delivery of molecules of polar drug speeches, which must be encapsulated. Faces encapsulated in liposomes are shown in Fig. 2.7. Amphiphilic and lipophilic molecules vary from phospholipid bisphere to sporidity to phospholipids. The formation of two-balloon neosomes is possible with the participation of non-ionic PAR instead of phospholipids.
Mal. 2.6.
Mal. 2.7.
Particularly technological problems should be put before the distributors of combined preparations, in order to avenge a sprinkling of active speeches, in order to ensure the optimal stimulation of different minds. Zrozumilo, although it may be taken up to the hour for the components, however, you can simply tablet the sum or, if necessary (for example, for the exchange of contact between the components during storage), forward granulation and encapsulation of the components. As the components require different sizes of SHKT for optimal soaking, the tablets are pressed from granules with different sizes. In this way, it is possible to use the technology of bagatospheric tableting or controlled tableting. Sound up to the warehouse of the combined medicinal product, do not include components that negatively affect the savings, mastering the pharmacological action of one alone.
Although the components of the complex preparation are due to be acquired at a different hour (although in one area of the mucosal-intestinal tract), there is no alternative to a divided dose.
Sublingual introduction vikoristovuyut for nitroglycerin, so that the drug is negligible to go to the deep bloodstream, bypassing the intestinal wall and the liver. However, the greater number of licks cannot be received in this way, because the stench is less active or may be more effective.
Rectal insertion vikoristovuyut in quiet moods, if ailments cannot be taken internally through boredom, the lack of coping, otherwise it is impossible for you (for example, after surgery). In rectal candles, LZ is mixed with a low-melting speech, as it is distinguished after insertion at the rectum. The thin mucous membrane of the rectum is well supplied with blood, so the drug is soaked up quickly, passing the liver during the first passage.
Injection way ( parenteral administration ) includes sub-shkirny, internal language and internal ways of introducing words. In contrast to oral administration, liquids, which are administered parenterally, drain the bloodstream, bypassing the intestinal wall and the liver, so the administration is accompanied by a greater swedish and positive reaction. Parenteral administration of vicorist for advancing situations: ailments cannot be taken internally, LZ can be ingested into the body with a small dose, and it’s also nasty and unstoppable.
At pіdshkіrnі іn'єktsії the needle is inserted under the skin, and the LZ is located at the capillary, and then it is carried away by the bloodstream. The introduction of vicory is not recommended for a variety of protein preparations, for example, insulin, which, when taken internally, is over-converted to the SCT. Treatments for such injections can be used as a suspension, or as indistinctly indistinct complexes: it is necessary to increase their intake in the blood (from a few years to a decade or more) and change the frequency of administration.
Yakshcho need to send a great obsyag LZ, internal language shorter than pidshkirnih injections. For such injections, vikoristovuyut doshu head.
At internal injections the needle should be injected directly into the vein. It is more important to vikonate technically in parallel with other methods of introduction, especially in people with thin, crumbly or sclerotic veins. The internal route of introduction is one-time injection or non-stop dropwise in the best way to deliver the faces for recognized fast and exact doses.
Transdermal injection vicorist for LZ, which can be introduced into the body for additional plaster, which is applied to the skin. Such faces, sometimes mixed with chemical speeches, which make it easier to penetrate through the skin, are consumed in the bloodstream without any hindrance, it’s right that without interruption, stretching rich years, days and days. However, for some people, on the shkіrі at the place of contact with the plastyr, there is a breakdown. In addition, with such an introduction, faces can come through the skin with insufficient speed. Transdermally administer only drugs that are prescribed at apparently low additional doses, for example, nitroglycerin (for angina pectoris), nicotine (for smoking), and fentanyl (for pain relief).
Deyakі liki, for example, gases, which can be used for general anesthesia, that can be introduced into the body for the treatment of bronchial asthma in the form of an aerosol inhalation route (inhale). The stench is consumed by the legend and the stars come from the bloodstream. So take a lot of preparations.
Absorption rate constant (Before a) characterizes the level of blood supply during the month of introduction at the blood.
The scheme of pharmacokinetics of medicinal drugs is shown in Fig. 2.8.
Mal. 2.8. Pharmacokinetics of medicinal products(scheme)
Rozpodil, metabolism, medical treatment
Rosepodil changes with increased penetration of the blood-brain barrier (meningitis, encephalitis, TBI, shock, caffeine intake, euphyllin) and decreased penetration of the blood-brain barrier (prednisolone, insulin).
Hydrophilic streaks are more likely to penetrate the blood-brain barrier (lower frequency of side effects on the CNS).
Rozpodil changes with supra-world accumulation of lip in tissues (lipophilic streaks) in obesity. The amount of dose given to the drug ( V d) characterize the degree of ingestion by tissues from blood plasma (serum). V d( V d =D/C 0) – brain volume, in which it is necessary to administer the entire dose of the drug that has been consumed in the body ( D ), sob mv sirovattsі blood (C0). Rospodil changes with hypoproteinemia (hepatitis, starvation, glomerulonephritis, summer age), hyperproteinemia (Crohn's disease, rheumatoid arthritis), hyperbilirubinemia.
The phases of biotransformation of medicinal products are presented in fig. 2.9. Metabolism of lipophilic drugs changes in case of liver pathology (it is necessary to reduce the dose or the frequency of administration), one-hour administration of a decilk of drugs. Rich in vitamins, zocrema vitamin B6, cofactors of enzymes that are metabolized by drugs. So, products, rich in vitamin B6, increase the level of splitting of levodopa. It reduces the concentration of dopamine in the blood. The virulence of the effects of antiparkinsonian drugs is changing. On the other hand, vitamin B6 deficiency may reduce the rate of metabolism of such drugs, such as isoniazid and others.
Global clearance of the drug (Z 1 t) characterizes the cleanliness of the purification of the organism in the form of a medicinal product. You can see nirkovy (Сlr) and pozanirkovy ( Cl er) clearance, yakі podrazhayut vyvedennya lіkarskoy ї chovina vіdpovіdno z sechey іnshimi slyahami (usamvredі іz zhovchyu). High ground clearance is the sum of the nir and lower clearance. Drinking period ( T 1/2) – an hour, the necessary change in the blood concentration of the drug in the blood, to deposit according to the constant of the liquidity of the elimination ( T 1/2 = 0,693/K el) . Constancy of dryness of elimination (Before el) that excretions (Before ate) to characterize the viability of the drug’s exposure to the body in a way of biotransformation and excretion, the severity of excretion from the cut, feces, and other. Elimination of hydrophobic drugs is changed in case of liver pathology (it is necessary to reduce the dose of drugs or the frequency of administration), heart failure.
Elimination of drugs is changed in the case of an one-hour prescription of drugs that halt the activity of microsomal liver enzymes (cimetidine). Reabsorption and secretion of electrolytes and non-electrolytes in the nephron are shown in Fig. 2.10.
- Kuznetsova N.V. Clinical pharmacology M., 2013.
- Katzung B. G. Basic and clinical pharmacology. M: Binom, 1998.
Details
Global pharmacology Pharmacokinetics
Pharmacokinetics- Razdіl pharmacology, attributions to the study of kinetic patterns of distribution of medicinal speeches. Vivchae vivilnennya likarsky speeches, smoky, rozpodil, deposition, transformation and vision of likarsky speeches.
Ways to introduce medicinal products
Vіd vіd vіd vіdnіnnya svydkіst vіdkіst razvitku efektu, yogo virazhenіst i trivalіst. In okremih vipadkah the way of zaprovadzhennya shows the nature of the speeches.
Separate:
1) enteral routes of introduction (through the herbal tract)
With these paths of introduction, the speech is well soaked through the path of passive diffusion through the membrane. That is why the lipophilic non-polar slugs and the filthy hydrophilic polar ones get wet.
Pіd movu (sublingual)
Smoktuvannya vіdbuvaєtsya very fast, speeches are sipped at the roof, passing the liver. However, the surface, which is wetted, is small, and in such a way it is possible to introduce only highly active speech, which are prescribed in small doses.
Butt: tablets of nitroglycerin, which should be taken 0.0005 g of nitroglycerin. Diya comes after 1-2 min.
Through the mouth (per os)
Likarsky speeches are simply forged. Moistening is often taken from the sluice, and even more from the small intestine (which is important to wet the surface of the intestine and intensively bleeding). The main mechanism of absorption in the intestines is passive diffusion. Smoktuvannya of the small intestine is good enough. It is necessary to deposit the type of intestinal motility, the pH of the medium, the quantity and quality of the intestines.
From the small intestine, the speech is drained through the system of the portal vein of the liver to the liver and only then - to the total blood circulation.
The absorption of speech is also regulated by a special membrane transporter - P-glycoprotein. Vіn spriyaє vyvedennya rechovin in the lumen of the intestine and pereskodzhaє їх absorption. Vіdomi іngіbіtori tsієї slovina - cyclosporine A, quinidine, verapamil, іtraknazol toshcho.
Following the memory that some medicinal speeches are not recognized internally, shards of stench roam in the intestinal tract under the action of the mucosal juice and enzymes. In such a situation (because the drug can stimulate the mucous membrane of the slough), it is prescribed in capsules or dragees, as they are only distributed in the small intestine.
Rectally (per rectum)
Significant part of the speech (about 50%) is found near the bloodstream, bypassing the liver. In addition, with this route, the speech is not subjected to the infusion of enzymes of the SHKT. Vsmoktuvannya vіdbuvaєtsya by way of simple diffusion. Rectally, speeches are prescribed as suppositories for enemas.
The medicinal language, which reflects the structure of proteins, fats and polysaccharides, does not get wet in the intestines.
Likewise, zastosovuyt podіbny way zaprovadzhennya i mіstsevoy vlivu.
2) parenteral routes of administration
The introduction of speeches, bypassing the herbal tract.
Pidshkirny
Speech can be wetted by a path of passive diffusion and filtration through interstitial spaces. With such an orbasis, under the skin, one can introduce both non-polar lipophilic and hydrophilic polar speech.
Ring out in a podshkirno way to introduce medicinal speeches. Other - oily varieties and suspensions.
Domestic language
Speech is soaked in the same way, like in the case of a subcutaneous introduction, ale shvidshe, the ossicles of the vascularization of the skeletal masses are more pronounced in the pores of the subcutaneous fat-fat tissue.
In m'yazi it is impossible to introduce hypertonic differences, like teasing speech.
At the same time, inject oils, suspensions into the ointment, in order to create a depot for the drug, with any medicinal speech, it can be wetted into the blood.
internally
The likar speech is immediately consumed by the blood, so it develops even more quickly - for 1-2 credits. In order not to make the concentration of speech in the blood too high, you should dilute it in 10-20 ml of isotonic sodium chloride and administer properly, with a decal of chvilin.
It is not possible to inject oil into a vein, call through the problem of blockage of the vessels!
Internally arterially
Allows you to create in the space, which is bled by this artery, to a high concentration of speech. In such a way, it is sometimes necessary to administer anti-tumor drugs. For a change in toxic toxicity, there may be piecewise difficulties with the blood with a path of applying a tourniquet.
intrasternal
Call vicorist for the technical impossibility of the internal introduction. Faces should be injected near the mouth of the sternum. The victorious method is for children and people of a frail age.
Internal
Rarely vikoristovuyut, as a rule, in operations. Diya is coming more quickly, shards of more faces are good to be wetted through the leaves of the line.
inhalation
The introduction of medical remedies by inhalation. So introduce gas-like speech, steamy air, aerosols.
The lungs bleed well, so it is easy to get wet.
transdermally
For the consumption of trivalo dії vysokolіpopіlnyh likarskih rechovina, yakі easily penetrate through neushkodzhenu shkir.
intranasally
For insertion into the empty nose at the sight of streaks or a spray from the rosary on the mіstsevu or resorptive dia.
Penetration of medicinal speeches through the membrane. Lipophilic non-polar speech. Hydrophilic polar speech.
The main ways of penetration are passive diffusion, active transport, facilitated diffusion, pinocytosis.
The plasma membrane is composed mainly of lipids, which means that less non-polar lipophilic speech can penetrate through the membrane through a path of passive diffusion. Navpaki, hydrophilic polar speech (GPS) practically does not penetrate through the membrane in such a way.
A lot of medicinal speeches with weak electrolytes. A part of such speeches is replaced by a non-ionized form, that is. in non-polar, and part - in looking ions, which carry an electric charge.
A part of a weak electrolyte penetrates through the membrane through a path of passive diffusion through the membrane
To evaluate the ionization of the vicorist, the pK a value is the negative logarithm of the ionization constant. Numerically, pK a is equal to pH, in which half of the molecules of the semiion are ionized.
For a specific degree of ionization of vicorist, use the Henderson-Haselbach formula:
pH = pKa+ - for basics
Ionization of the foundations in the way of their protonation
The ionization steps are defined as follows
pH \u003d pK a + - for acids
The ionization of acids follows the path of their protonation.
ON \u003d H + + A -
For acetylsalicylic acid pKa = 3.5. At pH = 4.5:
Also, at pH = 4.5, acetylsalicylic acid may be more dissociated.
Mechanisms of wetting speech
Likarsky speeches can penetrate into the clitina by a path:
Passive diffusion
The membrane has aquaporins, which allow water to enter the clitina and can pass in a path of passive diffusion along the concentration gradient of the difference in the water hydrophilic polarity of the speech with even small sizes of molecules (the aquaporins are narrow). However, this type of occurrence of medicinal speeches in clitinum is rather rare, since the expansion of the greater number of molecules of medicinal speeches outweighs the diameter of aquaporines.
In the same way, through simple diffusion, non-polar lipophilic speech penetrates.
active transport
Transport of medicinal hydrophilic polar speech through the membrane against the concentration of the gradient behind the help of a special carrier. Such transport is vibrational, and it will require a lot of energy.
The medicinal speech, which can be related to the transport protein, connects with the binding sites of the transporter from one side of the membrane, then the conformation of the transporter changes, and, nareshti, the speech changes side of the membrane.
Easier diffusion
Transport of hydrophilic polar speech through the membrane by a special transport system following a concentration gradient, without energy gain.
Pinocytosis
Expansion of the clitin membrane, such as molecules of speech and vesicles, as they pass through the cytoplasm of the clitin and vilify the speech from the lower side of the clitin.
Filtration
through the pores of the membranes.
So the value filtration of medicinal speeches through interstitial spaces.
Filtration of HPV through interstitial spaces may be important in the case of inoculation, rozpodil and bred and fallow:
a) the size of the inter-client intervals
b) the size of the speech molecules
1) through the gaps between the clitins of the endothelium in the capillaries of the nirk glomeruli in the path of filtration, it is easy to pass most of the medicinal speeches, which are in the blood plasma, as the stench is due to the proteins of the plasma.
2) in the capillaries and venules of the subcutaneous fat cells, skeletal masses, the spaces between the cells of the endothelium are sufficient for the passage of a large number of medicinal cavities. Therefore, with the introduction of the skin, or in the ointment, it is good to soak and penetrate the blood and non-polar lipophilic speech (path of passive diffusion in the lipid phase), and hydrophilic polarity (path of filtration and passive diffusion ї in the aqueous phase through interstitial spaces between cells of the endothelium).
3) with the introduction of HPV in the blood, the speech easily penetrates into most tissues through gaps between capillary endotheliocytes. Vignettes of speech, for which they use active transport systems (anti-parkinsonian drug levadopa) and tissues, water-silicon blood-hystohematic barriers. Hydrophilic polarities of speech can penetrate through such barriers only in certain areas, in such barriers there are few turns (in the area postrema of the douglas brain, HPV penetrates into the trigger zone of the vomiting center).
Lipophilic non-polar speech easily penetrates the central nervous system through the blood-brain barrier by passive diffusion.
4) In the epithelium of the HKT, the intercellular spaces are small, so the HPV is badly wetted by him. So, the hydrophilic polar speech of neostigmine under the skin is prescribed at a dose of 0.0005 g, and for the treatment of a similar effect with recognized internally, a dose of 0.015 g is required.
Lipophilic non-polar speech is easily soaked from the mucosal-intestinal tract in a path of passive diffusion.
Bioavailability. Presystemic elimination.
In connection with the fact that systemic speech develops only when it enters the bloodstream, the signs of it come from the tissue, the term "bioavailability" is proponated.
The liver has a lot of speeches, biotransformations occur. Often speech can be seen in the intestines from the stomach. To that very roof you can spend less than a part of the speech, what to introduce, reshta piddaetsya elimination during the first passage through the liver.
Elimination- biotransformation + excretion
In addition, faces may not be absorbed in the intestines, metabolized in the intestinal wall, and often removed from it. All at the same time with elimination during the first passage through the liver is called presystemic elimination.
Bioavailability- a small amount of unchangeable speech, which I drank in a deep bloodstream, in a hundred years before the introduction of a quantity.
As a rule, bioavailability values are assigned to dovidniks, while they are recognized in the middle. For example, the bioavailability of propranolol is 30%. Tse means that with intravenous administration at a dose of 0.01 (10 mg) only 0.003 (3 mg) of unchanged propranolol is consumed in the blood.
To determine the bioavailability of the face, inject it into a vein (with the intravenous method, the bioavailability of speech becomes 100%). Through the intervals of time, the concentration of speech in the blood plasma is determined, then the curve of the change in the concentration of speech in the hour will be determined. Then we administer the same dose of speech internally, determine the concentration of speech in the blood and develop a curve. Vymiryuyut area under the curves - AUC. Bioavailability - F - is indicated as an indication of AUC when administered internally to AUC when administered intravenously, it is indicated in women.
bioequivalence
With the same bioavailability of the two speeches, the speed of their occurrence to total blood circulation can be different! Vidpovidno will be different:
Hour to reach peak concentration
The maximum concentration in blood plasma
Rozmir pharmacological effect
Himself to introduce the concept of bioequivalence.
Bioequivalence - means similar bioavailability, peak diї, nature and magnitude of the pharmacological effect.
Rozpodіl likarsky speeches.
When lipophilic speech gets into the bloodstream, it sounds differently in the body, and hydrophilic polarity - unevenly.
A direct influence on the character of the speech subdivision may be biological bars, as if they are streaked on the path: capillary walls, clitin and plasma membranes, hemato-encephalic and placental bars іtinnі promizhki").
The endothelium of the capillaries of the brain is not available for an hour, there is practically daily pinocytosis. The same role is played by astroglіy, like pushing the bar'ern force.
Hematoophthalmic barrier
Pereskodzhaє penetration of hydrophilic polar speech from the blood near the tissue of the eye.
Placental
Transition of the penetration of hydrophilic polar speeches from the mother's body into the fetus's body.
To characterize the distribution of the medicinal speech in the system of a single-chamber pharmacokinetic model (the body is mentally represented as a single space, the homeland. With the introduction of the medicinal speech, it is mittevo and evenly distributed) syag rozpodіlu, scho daetsya - V d
Let's agree to a rozpodil vіdbivaє approximate obsyag rіdini, yakom rozpodіlyaє speech.
As for the medicinal speech V d = 3 l (blood plasma volume), it means that the speech is found in the blood plasma, does not penetrate into the blood cells and does not go beyond the boundaries of the bloodstream. Possibly, this is a high-molecular speech (V d for heparin = 4 l).
V d \u003d 15 l means that the speech is found in the blood plasma (3 l), intercellular fluid (12 l) and does not penetrate into the tissue cells. Ymovirno, hydrophilic polar speech.
V d \u003d 400 - 600 - 1000l means that the amount is deposited in peripheral tissues and the concentration in the blood is low. For example, for imipramine - a tricyclic antidepressant - V d = 23 l / kg, that is approximately 1600 liters. This means that the concentration of imipramine in the blood is already low and that hemodialysis is not effective when imipramine is used.
Deposit
In case of rozpodіlі lіkarskoї ї speech in the body, parts can be trimmed (deposited) in different tissues. From the depot of the speech, it vibrates in the blood and may be pharmacologically determined.
1) Lipophilic speech can be deposited in fatty tissue. Application for anesthesia thiopental-sodium leads to anesthesia with a trivality of 15-20 minutes, so that 90% of thiopental-sodium is deposited in fatty tissue. After the induction of anesthesia, there is an anesthetic sleep for 2-3 years at the link with viability of thiopental-sodium.
2) Tetracyclines are deposited for three hours at the bone tissue. That is not assigned to children up to 8 years old, shards can destroy the development of brushes.
3) Deposition, tied from blood plasma. In combination with plasma proteins, speech does not show pharmacological activity.
Biotransformation
At the same time, one can see only a high-level ionization half-life, inhalation anesthesia.
Biotransformation of a large number of speeches occurs in the liver, where high concentrations of speeches are created. In addition, biotransformation may be required in legenia, nirkah, intestinal walls, and skinny.
Separate two main views biotransformation:
1) metabolic transformation
The transformation of speeches for oxidization, renewal and hydrolysis. Oxidation is mainly due to microsomal oxidases, which are affected by NADP, acidifying cytochrome P-450. Reinforcement is observed under the influx of the nitro- and azoreductase system only. Hydrolyze, as a rule, esters, carboxylesterases, amidases, phosphatases, etc.
Metabolites, as a rule, are less active, less active than speech, but others are active for them. For example: enalapril is metabolized to enaprilat, which may affect the hypotensive effect. However, the wine is badly wetted out of the mucosal-intestinal tract, so it is suggested to be administered intravenously.
The metabolites can be toxic for speech. The metabolite of paracetamol is N-acetyl-para-benzoquinoneimine in case of overdose resulting in liver necrosis.
2) conjugation
Biosynthetic process, which is accompanied by the advent of medicinal speech or metabolites of low chemical groups or molecules of endogenous spores.
Process to go either one by one, or it will go well!
Razrіznyayut also:
- specific biotransformation
Ocremium enzyme is added one by one, showing substrate activity at its own temple. Example: methyl alcohol is oxidized by alcohol dehydrogenase with dissolved formaldehyde and formic acid. Ethyl alcohol is also oxidized by aclogold dehydrogenase, but affinity to ethanol to the enzyme is significantly higher, lower to methanol. Therefore, ethanol can improve the biotransformation of methanol and change its toxicity.
- nonspecific biotransformation
Under the influx of microsomal liver enzymes (most importantly, oxidase of disturbing functions), localized in smooth-surfaced cells of the endoplasmic reticulum of the liver cells.
As a result of biotransformation, lipophilic uncharged speech sounds like a hydrophilic charge, which is easily excreted from the body.
Vivedennya (excretion)
Medicinal speeches, metabolites and conjugates, are mainly derived from the section and the zhovchyu.
-Z section
In nirks, low molecular weight layers, different in plasma (not associated with proteins), are filtered through the membranes of the capillaries of the glomeruli and capsules.
Also active is the secretion of speech in the proximal tubule for the participation of transport systems. In this way, organic acids, salicylates, penicillins are seen.
Speech can help to see one another.
Lipophilic uncharged speech is reabsorbed by passive diffusion. Hydrophilic polars are not reabsorbed and removed from the section.
High pH value. For an accelerated removal of sour slugs, change the reaction of the section varto into puddle, and for the removal of bases - at sour.
- zhovchyu
This is how tetracyclines, penicillins, colchicine and in. Qi preparations are significantly seen in live, then often excreted in excrement, or reabsorbed ( intestinal-liver recycling).
- from the secrets of the springs
I especially respect the varto animal for those who, during the period of lactation, see a lot of speeches as milky ridges, as if they were mothers who are ready.
Elimination
Biotransformation + excretion
To characterize the process of vicoration, a number of parameters are used: the constant of whiteness of elimination (К elim), the period of napіvelіmіnіnation (t 1/2), the clearance clearance (Cl T).
The constant of dryness of elimination - Before elim- Vіdbivaє shvidkіst vydalennya speechovi z organism.
The period of application - t 1/2– at the right time, the required decrease in the concentration of speech in plasma by 50%
Butt: a 10 mg dose of speech A was injected at the vein. The rate constant of elimination is 0.1/year. For a year in plasma, 9 mg is lost, for two years - 8.1 mg.
Clearance - Cl T- The amount of blood plasma that is cleared from speech in one hour.
Razrіznyayut nirkovy, liver and scorched clearance.
With a constant concentration of speech in the blood plasma, the nirkovy clearance - Cl r is displayed as follows:
Cl \u003d (V u x C u) / C p [ml / min]
De Cu і C p - concentration of speech in the section of blood plasma, apparently.
Vu - shvidk_st sechovidіlennya.
Hot clearance Cl T depends on the formula: Cl T = V d x K el
The deep clearance shows how part of the obyagu rozpodіlu zvіlnyaєtsya in speech at one hour.
Soaking (absorption) - the transfer of medicinal speech from the month of introduction in the systemic bloodstream. Naturally, with the enteral method of introducing LZ, it develops in the medicinal form, through the epithelial cells, the PCT is taken into the blood, and then it is already distributed throughout the body. However, in case of parenteral pathways for the introduction of LZ, in order to consume until the moment of realization of its pharmacological effect, it may, at least, pass through the endothelial vessel, so that in case of any method of administration to reach the target organ, the drug must penetrate through various human biological membranes of epithelial and (or ) endothelial cells.
The membrane is represented by a bilayer of lipids (phospholipid) permeated with proteins. Skin phospholipids may have 2 hydrophobic “tails”, the middle middle, and the hydrophilic “head”.
Іsnuє kіlka options for the passage of medicinal speech through biological membranes:
passive diffusion.
Filtration through pores.
active transport
Pinocytosis.
Passive diffusion - The main mechanism of antibiotic smudging. The transfer of drug speech occurs through the lipid membrane along the concentration gradient (from the area of higher concentration to the area of lower concentration). In which molecular range is lesser than the value of filtration (Fig. 2).
Mal. 2. Passive diffusion
Officials, what to add to the speed of passive diffusion:
On top of the soaking(The main part of the inoculation of the greater part of the LZ is the proximal part of the small intestine).
blood flow in the small intestine, the vein is larger, lower in the sac, so it is more wet.
Contact hour LZ from the smoky surface (when the intestinal peristalsis becomes stronger, the smoky veins change, and when weakened, they increase).
Steps of diversity LZ in lipids (the membrane streaks against lipids, then lipophilic (non-polar) speech is more often wetted).
Steps of ionization LZ. Although LZ, at pH values, the most powerful mediums in the body, is the main rank in the non-ionized appearance, it differs more in lipids and penetrates better through biological membranes. As speech is ionized, it rottenly penetrates through the membranes, but I can reduce the water gap.
concentration gradient.
Tovshchina membrane.
Rіdini organism for physiological minds wash pH 7.3–7.4. The lower pH may be in place of the intestinal duct, cutting, inflamed tissues and tissues in the hypoxia station. The pH of the medium determines the degree of ionization of molecules of weak acids and weak bases (weak bases in the middle of LZ more, lower weak acids) according to the Henderson-Hasselbach formula.
For weak acids:
for weak substituents:
Knowing the pH of the medium and pKa of the speech (table data), one can determine the levels of ionization of the licks, and therefore, the levels of iodine absorption from the mucosal intestinal tract, reabsorption or excretion by nirkami at different pH values with read.
It is clear that the non-ionized forms of atropine in the acid medium of the tube are significantly less than the number of non-ionized ones (10 7,7 ionizations), which means that it will not be practical to get wet at the vein valve.
butt 2.
Significantly, phenobarbital (pKa 7.4) will be reabsorbed in the "acidic" section (pH 6.4). Phenobarbital is a weak base.
It is evident that the non-ionized molecules of phenobarbital in our minds are 10 times less, lower ionized, and also badly reabsorbed in the "sour" section and good to be present.
In case of an overdose of phenobarbital, acidification is one of the methods to combat intoxication.
Filtration bath zdіysnyuєtsya through the pores, which are between the cells of the epidermis of the mucous membrane of the mucosal tract, horns, endothelium of the capillaries and so on (most of the capillaries of the brain do not have such pіr (Fig. 3)). The epithelial cells are separated by narrow gaps, through which only small water molecules (sechovin, aspirin, and iodine) can pass.
Mal. 3. Filtration
active transport - Tse transport LZ against concentration gradient. For which type of transport, energy efficiency is required and the presence of a specific transfer system (Fig. 4). The mechanisms of active transport are highly specific, stinks were formed in the process of evolution of the organism and the necessary implementation of its physiological needs. As a result, this LZ, which penetrates through the cellular membranes for additional active transport, is close in its chemical structure to natural speech for the body (for example, cytostatic agents are analogues of purines and pyrimidines).
Mal. 4. Active transport
Pinocytosis . The essence of yoga lies in the fact that the speech is transported in contact with the singing space on the surface of the membrane and that the space is bending in the middle, the edges of the burial are stooling, the bulb is being settled with the speech, which is being transported. The veins appear on the outer surface of the membrane and are transferred to the middle of the cell (suggesting phagocytosis of microbes by macrophages). The medicinal speech, the molecular weight of which exceeds 1000, can only enter the clitina for additional pinocytosis. Fatty acids, protein fragments, vitamin B12 are transferred in this way. Pinocytosis plays an insignificant role in the inoculated licks (Fig. 5) .
Mal. 5. Pinocytosis
The listed mechanisms “practice”, as a rule, in parallel, but the most important contribution sounds like one of them. Yakiy same - to lie in the place of introduction and physical and chemical powers of LZ. So, in the empty mouth, the head rank, passive diffusion is realized, in a smaller world - filtration. Other mechanisms are practically not a problem. In the small intestine, there is no change in the implementation of all visceral manifestations of the inoculation mechanisms. In the small intestine and rectum, the processes of passive diffusion and filtration prevail. The stench is the main mechanism of soaking the LZ through the skin.
Option 2. (Inaccurate)
inhalation way to introduce the following medicinal forms:
aerosols (β-agonists);
gas-like speech (flying anesthetic agents);
finely dispersed powders (sodium cromoglycate).
The Danish method of administration ensures both medical (adrenomimetics) and systemic (preparation for anesthesia) dialysis. Inhalations of liquids work for additional special equipment (in the form of the simplest spray cans for self-sufficiency, we are ill to stationary devices). Vrahovyuchi tight contact on the surface, which is inhaled from the blood, as well as the majestic alveolar surface, the smoothness of the resorption of the face in the arch of the temple. Do not inhaler zastosovuyt likarski zasobi, scho mayut drіvlivі vlastivostі. It is necessary to remember that when inhaling speech, it is necessary to reach the left heart through the legs of the vein, which is done for the manifestation of a cardiotoxic effect.
Advantages of the way:
Swedish development of the effect;
the possibility of accurate dosing;
the presence of presystemic elimination.
Shortcomings of the method:
the need to use folding technical outbuildings (anesthesia devices);
pozhezhna nebezpeka (kysen).
Global pharmacology Pharmacokinetics. Ways and ways of introducing medicinal speeches into the body.
The subject of the task of clinical pharmacology.
Clinical pharmacology (KF)- a science that develops the principle of effective and safe pharmacotherapy, the means of determining the clinical value of the optimal zasosuvannya of medical benefits (LP).
The subject of clinical pharmacologyє faces for the minds of clinical practice.
Pharmacokinetics- change the concentration of medicinal speeches in the middle of the body of a healthy and sick person, as well as the mechanisms for the help of such changes.
Pharmacokinetics - inoculation, rozpodil, deposition, transformation
that vision of medicinal speeches.
All ways of introducing drugs into the body can be divided into enteral and parenteral. Enteral routes of introduction ( enteros- intestines) to ensure the introduction of the drug into the body through the mucous membranes of the intestinal tract. To the enteral pathways, the introduction is carried out:
· Oral administration (inside, per os)- The introduction of drugs into the body with a path forged. At the same time, the intestines are pulled into the tube, and for a stretch of 30-40 minutes, it is soaked in the system of the portal vein. Far away from the blood stream, the faces go to the liver, then to the lower empty vein, right hearts and hearts, nareshti, little blood flow. In this way, it is most common to administer solid and rare medicinal forms (tablets, dragees, capsules, tablets, lozenges, etc.).
· Rectal path (per rectum)- Introduction of liquor through the anal opening into the ampulla of the rectum. This way to introduce mild medicinal forms (suppositories, ointments) or other (for additional microclysters). Smoktuvannya speech zdіysnyuєtsya in the system of hemorrhoidal veins. The rectal passageway often zastosovuetsya in children of the first three years of life.
· Sublingual (under tongue) and subbuccal (empty between clear and sharp) introduction. In such a way to introduce solid drug forms (tablets, powders), drugs from rare forms (various) and aerosols. With these methods of introduction, the medicinal zasib is soaked up at the vein of the mucous membrane of the empty mouth and then successively come near the upper empty vein; After that, the faces are delivered to the left heart and with arterial blood to reach the target organs.
Parenteral administration - a route for the introduction of a medicinal product, when it enters the body, bypassing the mucous membranes of the intestinal tract.
· Injection introduction. With this route, the faces are immediately consumed in the systemic blood flow, bypassing the tributaries of the portal vein and the liver. Prior to the injection, there are all methods, for which the integrity of the curved tissues is taken into account. The stench zdіysnyuyutsya for help syringe and needles.
· Internal introduction. With this method of introduction, the needle of the syringe pierces the skin, hypodermis, vein wall and faces without intermediary injection into the systemic bloodstream (lower or upper empty veins). Faces can be administered in a strum-like manner, or in a quick (bolus) way, as well as in a dripping way.
· Internal language introduction. Danim way to introduce all sorts of rare medicinal forms and powders. The needle of the syringe is used to pierce the skin, hypodermis, fascia of the skin and sweat the torso, where and pierce the faces. The effect develops in 10-15 minutes. The volume of the difference to be administered is not to blame for revisiting 10 ml. With intravenous injection, the faces are wetted less equally with intravenous injections, and more often, lower with oral ingestion.
Inhalation introduction- The introduction of likarskoy speech by way of inhalation of її pairs or other particles.
Transdermal injection- application on the skin of the medical speech for the security of systemic activity.
Misceve applied. Includes application of faces on the skin, mucous membranes of the eyes (conjunctiva), nose, larynx.
Mechanisms of soaking up medicinal speeches.
Vsmoktuvannya- The process of overcoming LZ from the month of entry into the blood. When smoking the medicinal speech, lie in the way of introducing yoga into the body, medicinal form, physical and chemical authorities (variability in lipids or hydrophilicity of the speech), as well as in the intensity of blood flow in the introduction.
LZ, taken orally, are smoky, passing through the mucous membrane of the mucosa of the mucus-intestinal tract, which is characterized by their difference in lipids and the stage of ionization. There are 4 main mechanisms of activation: diffusion, filtration, active transport, pinocytosis.
Passive diffusion occurs through the clitin membrane. It is wetted until quiet fir, until the concentration of medicinal speech from both sides of the biomembrane is not observed. In a similar order, lipophilic speech (for example, barbiturates, benzodiazepines, metoprolol, etc.) are wetted, moreover, they are more lipophilic, more active than their penetration through the clitin membrane. Diffusion of speeches is passive even without the loss of energy behind the concentration gradient.
Diffusion is simplified - the transport of drug speeches through biological membranes through the participation of molecules of specific carriers. In case of any transference, the liquids are also affected by the concentration gradient, but the degree of transference is significant. For example, cyanocobalamin is smeared in such a manner. In yoga diffusion, a specific protein takes part - gastromucoprotein (Castle's internal organ), which settles into the tube. If the products of the colon are damaged, then the intake of cyanocobalamin decreases, and as a result, pernicious anemia develops.
Filtration works through the pores of cellular membranes. This mechanism of passive soaking, without any energy loss, operates behind the concentration gradient. Characteristic for hydrophilic speeches (for example, atenolol, lisinopril and in), as well as ionized spoluk.
Active transport is due to the participation of specific transport systems of cellular membranes. In view of passive diffusion and filtration, active transport is an energy and building process against a concentration gradient. In this way, a sprinkling of speeches can compete for the same transport mechanism. Ways of active transport may have a high specificity, shards were formed in the process of tribal evolution of the body for the provision of its physiological needs. The very same mechanisms are the main ones for the effective delivery of live speech and the appearance of products in the exchange.
Pinocytosis (corpuscular absorption or pensorption) is also a different type of exposure to excess energy, which can lead to a concentration gradient. In case of occlusion of the drug speech and invagination of the clitin membrane with the established vacuoles, as a direct line to the protylogenous side of the cell, exocytosis deviates from the development of the drug side.
Pharmacokinetics
Pharmacokinetic processes - soaking, rozpodil, deposition, biotransformation and withdrawal - related to the penetration of HL through biological membranes (mainly through the cytoplasmic membranes of clitin). There are such ways of penetration of speech through biological membranes: passive diffusion, filtration, active transport, facilitated diffusion, pinocytosis (Fig. 1.1).
^ passive diffusion. Through a passive diffusion path, the speech penetrates the membrane following a concentration gradient (for example, the concentration of speech from one side of the membrane is higher, lower from the other, the speech moves through the membrane from a higher concentration to a lower one). This process does not require any energy. Shards of biological membranes are most importantly folded with lipids, in such a way they can easily penetrate the speech, the difference between lipids and yak may be charged, tobto. l i -pofilnі non-polar speech. First of all, hydrophilic polarity practically does not penetrate through lipid membranes without intermediary.
As for weak electrolytes - weak acids or weak bases, then the penetration of such rhechovins through the membranes is formed as a stage of їх ionization, so as a way of passive diffusion through the subvariant lipid ball of the membrane it is easy to pass only non-ionized (uncharged) speech molecules.
The ionization steps of weak acids and weak bases are:
pH values of the medium;
ionization constant (K a) of speech.
HA^H + + A~
Luzhne middle
Ionization of weak bases
BH + ^ B + H +
The ionization constant characterizes the structure of the speech to ionization for the singing value of the pH of the medium. In fact, to characterize the soundness of speeches before ionization, the indicator of pK a, which is the negative logarithm of Ka (-lg Ka), is used. The indicator pKa is numerically equal to the pH value of the medium, at which half of the molecules of this speech are ionized. The values of pKa for weak acids, as well as for weak substations, vary at the boundaries. The smaller the pKa of a weak acid, the easier it is to ionize at apparently low pH values of the medium. Thus, acetylsalicylic acid (pK a = 3.5) at pH 4.5 is ionized more lower by 90%, at the same time, the ionization steps of ascorbic acid (pK a = 11.5) at the same pH value become frequent% (Fig. 1.2). For weak foundations, there is a turnaround. The more RCA of a weak base, the greater the world it is ionized to induce at apparently high pH values of the medium.
The ionization step of a weak acid or a weak base can be developed according to the Henderson-Hasselbalch formula:
This formula allows you to designate, which will be the level of penetration of LH (weak acids or weak bases) through the membranes, which separates the middle of the body with different pH values, for example, when the drug is wetted from the tube (pH 2) into the blood plasma (pH 7.4).
Passive diffusion of polar hydrophilic rivers is possible through water pores (Fig. 1.1). Chain proteins in the membrane of clitin, penetrating for the leader of the speeches. However, the diameter of water pir is small (about 0.4 nm) and only small hydrophilic molecules (for example, sechovin) can penetrate through them. The majority of hydrophilic medicinal cavities, the diameter of molecules of which is over 1 nm, do not pass through water pores in the clitin membrane. Therefore, most of the hydrophilic medicinal speeches do not penetrate the middle of the cells.
Filtration bath- this term vicorous as well as the penetration of hydrophilic rhechovins through water pores in the clitin membrane, so also their penetration through the intercellular spaces. Filtration of hydrophilic speeches through interstitial spaces is carried out under a hydrostatic and osmotic vice. This process is of great importance for the introduction, distribution and development of hydrophilic plants and deposits depending on the size of the intermediary deposits.
Since interstitial spaces in different tissues are not the same in size, hydrophilic drugs in different ways of introduction are mixed differently and are distributed unevenly in the body. For example, about
Between the membranes between the epithelial cells of the intestinal mucosa are small, which facilitates the absorption of hydrophilic LB from the intestines into the blood.
Interstices between endothelial cells of vessels of peripheral tissues (skeletal membranes, subcutaneous cells, internal organs) can achieve large diameters (about 2 nm) and pass more hydrophilic L, so that it is safe to achieve penetration nya Lz tissue in the blood and blood in the tissue. At the same hour in the endothelium of the vessels of the brain of the intercellular spaces are daily. Endothelial clitiny closely adhere one to one, making a barrier (hematoencephalic barrier), which allows the penetration of hydrophilic polar speeches from the blood into the brain (Fig. 1.3).
^ active transport zdіysnyuєtsya for the help of special transport systems. Sound protein molecules that penetrate the cell membrane (div. Fig. 1.1). Speech connects with a carrier protein from the outer side of the membrane. Under the influx of ATP energy, a change in the conformation of the protein molecule occurs, which leads to a change in the strength of the bond between the carrier and the speech, which is transported, and the development of the speech from the inner side of the membrane. In this way, hydrophilic polar speech can penetrate into the clitina.
Active transport of speeches through the membrane may have advancing characteristics: specificity (transport proteins
Carry through the membrane less than the songs of speech), insufficiency (when all proteins-carriers are connected, the quantity of speech, which is transported through the membrane, does not increase), it is against the concentration gradient, vimage energy ї (this is due to metabolic otters).
Active transport takes part in the passage through the clitin membrane of such speeches, which are necessary for the life of clitin, as amino acids, zucru, pyrimidine and purine bases, salt, vitamins. Deyakі hydrophilic likarsky speech permeate through the membranes of clitin for additional active transport. Qi L are connected with the same transport systems, yakі zdіysnyuyut transfer through the membranes of the vischetransferred spoluk.
^ Improved diffusion - transfer of speech through membranes for the help of transport systems, which is carried out behind a concentration gradient and does not require energy. So, as an active transport, diffusion is facilitated - it is specific in terms of the transition to singing speeches and the process that occurs. This transport facilitated navigation near the climate of the hydrophilic polar rivers. In this way, glucose can be transported through the clitin membrane.
Cream of proteins-carriers, yakі zdіysnyuyut transmembrane transfer of speech in the middle of the cells, in the membranes of rich cells - transport proteins. P-glycoproteins, to hide away from the clitin of alien spolks. P-glycoprotein pump of manifestations in the epithelial cells of the intestine, in the endothelial cells of the vessels of the brain, which regulate the blood-brain barrier, in the placenta, liver, nirkah and other tissues. These transport proteins pereshkodzhayut soaked in some speeches, their penetration through the histohematic barriers, add to the introduction of speeches from the body.
Pinocytosis(Type Greek. pino - p'yu). Large molecules, or aggregates of molecules, stick together from the outer surface of the membrane and are separated by it from the closed bulbs (vacuoles), as they are water-creamed in the membrane and burrow into the middle of the cell. In the distance, the small patches can wriggle in the middle of the cell, or from the lower side of the cell, they are called a path to exocytosis.
^ 1.1. Smoktuvannya likarsky speeches
Vsmoktuvannya(Absorption, in lat. absorbeo - vmoktuyu) - a process, as a result of some kind of speech, it is necessary to enter the blood and / or lymphatic system after a month. The infusion of the drug begins immediately after the introduction of the drug into the body. In addition, by some way the drug is introduced into the body, deposit swidkіst i stupіn yogo somktuvannya, and zreshtoj shvidkіst nastannya effect, yogo value that trivalіst.
^ Ways to introduce medicinal products
Separate enteral(through the grass tract) that parenteral(bypassing the grassy tract) paths for the introduction of medicinal products.
A. Enteral routes of introduction
To enteral (type Greek. ento - in the middle enteron - gut) ways of introduction are seen:
sublingual (sublingual);
transbuccal (for chocus);
oral (in the middle, per os)\
rectal (through the rectum, per rectum).
Sublingual and transbuccal routes introduced a number of positive figures:
the stench is simple and good for the sick;
speeches, introduced sublingually or transbuccally, do not respond to the infusion of hydrochloric acid;
Speech is consumed in a deep bloodstream, passing the liver, which will avoid the hourly ruin and vision of the stomach, so that the titles of the effect of the first passage through the liver (div. side 32) are so acquired;
due to a good blood supply of the mucous membrane of the empty mouth, it is necessary to soak it up quickly, which will ensure the smooth development of the effect. Tse allow vikoristovuvaty such ways zaprovadzhennya in case of unfavorable camps.
Oral administration. With the introduction of medicinal products internally, the main mechanism for the absorption of drugs is passive diffusion - this way, non-polar speech is easily absorbed. The soaking of hydrophilic polar rhechovins is surrounded by a small amount of interstitial spaces in the epithelium of the SKT. Not a lot of hydrophilic drugs (levodopa, less pyrimidine - fluorouracil) are soaked in the intestines by way of active transport.
The soaking of weakly acidic substances (acetylsalicylic acid, barbiturates, etc.) begins already in the shell, in the acidic medium, most of the speech is unionized. Ale is mainly absorbed by all LH, including weak acids, in the intestines. This spray is large on the surface of the mucous membrane of the intestine (200 m 2) and intensive blood flow. Weak bases are absorbed more quickly in the intestines, lower weak acids, so that in the puddle middle of the intestine, weak bases are mainly replaced by non-ionized forms, which makes it easier to penetrate through the membranes of epithelial cells.
On the soaking of the medicinal speeches, they pour in their healthiness by the water (for the purpose of soaking up the speech, the guilt is divided in the intestines), the separation of the particles of the speech and the medicinal form, in a yakіy yoga is prescribed. When solid drug forms (tablets, capsules) are stagnant, the amount of dryness is great, with such a stench they disintegrate in the intestines. Shvydka razpadn_st of tablets (or capsules) will reach the highest concentration of speech in the mouth. To improve the consumption of the mixture of higher constant concentrations of drugs, vicorist medicinal forms with the improvement (controlled) of the drugs. In this rank, you can take away the preparations of the so-called prolonged drug, yakі, on the vіdmіnu vіd zvuchaynykh preparatіv, dіyut more richly.
(The calcium channel blocker nifedipine in typical drug forms is prescribed 3 times per doba, and for prolonged use 1-2 times per doba).
Taken internally medicinal speech is given infusion of hydrochloric acid and herbal enzymes in the intestinal tract. So, for example, benzylpenicillin is destroyed by hydrochloric acid of shell juice, and insulin and other speech of the polypeptide structure - by proteolytic enzymes. In order to avoid the destruction of certain speeches under the influence of acid and chloride-water juice, they are prescribed in special dosage forms, and in itself in tablets or capsules with acid-resistant coatings. Such drug forms pass through the duct without change and only disintegrate in the small intestine (intestinal drug forms).
Other factors can be added to the smoking of the PV in the SHKT. Zokrema, it's free to lie in the form of SHKT motility. Thus, the ingestion of LH, especially weak bases (propranolol, codeine, etc.), which in the puddle of the middle of the intestine are found more importantly in a non-ionized form, is more intense in case of an early depletion of the tube (for example, with a congested gastrokine tic metoclopramide). A reversal effect is observed with the introduction of speech that deforms the tube, such as M-anticholinergic (for example, atropine). At the same time, the strengthening of intestinal motility and, henceforth, a quick passage through the intestines can destroy the soaking of speeches, which are properly soaked.
The amount of that yakіsny warehouse in the place of the intestines is also added to the inoculation of the HL in the ICT. Warehouse components can disrupt the soaking of medicinal speeches. So, calcium, which is found in a large number of dairy products, forms complexes with tetracycline antibiotics, which are badly wetted. Tannin, which is removed from tea, is used with preparations for the release of non-specific tannin. Deyakі likarski zasobi suttєvo vplyvayut on smoktuvannya іnshih HL, yakі are administered at once. So, kolіs-tiramin (zastosovuєtsya in atherosclerosis to reduce the level of atherogenic lipoproteins) appears in the intestines of fatty acids and in such a way changes the appearance of adipose tissue, zocrema vitamins K, A, E, D. In addition, in n pereshkodzhaє smoking with thyroxine, warfare and others LH.
From the small intestine, the speech is soaked at the portal (portal) vein and from the blood stream, the kidney is taken from the liver and less sweat from the systemic bloodstream (Fig. 1.4). In the liver, more LVs are often biotransformed (and if they are inactivated) and/or they are seen with zhovchyu, so only a part of the speech comes into the systemic bloodstream, which is wetted. This process is called the effect of the first passage through the liver or elimination during the first passage through the liver (elimination includes biotransformation and elimination).
In connection with the fact that medicinal speech can have a resorptive effect, only after the stench has reached the systemic bloodstream (and then spread through the organs and tissues), to introduce understanding bioavailability.
Bioavailability- part of the administered dose of medicinal speech, which, apparently, reached the systemic circulation. Bioavailability is pronounced in vіdsotkah. The bioavailability of speech with intravenous administration is 100%. When administered internally, bioavailability is usually less. Dovodkovіy literature should suggest the importance of bioavailability of medicinal speeches for internal administration.
When administered internally, the bioavailability of medicinal speeches may be reduced for various reasons. Deyakі speechovina often collapse under the influx of hydrochloric acid and / or herbal enzymes in the intestinal tract. Acting drugs are not sufficiently well absorbed in the intestines (for example, hydrophilic polar substances) or they do not succumb to tableting drug forms, which can also be the cause of their low bioavailability. Vіdomi chovini, yakі metabolizuyutsya in the intestinal wall.
In addition, there is a lot of speech before it, as it is consumed in the systemic bloodstream, it is necessary to have even more intensive elimination during the first passage through the liver and because of this, the reasons may be low bioavailability. Obviously, the doses of such drugs when administered intravenously should change the doses necessary to achieve the same effect when administered parenterally or sublingually. So, nitroglycerin, which is practically absorbed from the intestines, but during the first passage through the liver is eliminated more by 90%, is administered sublingually at a dose of 0.5 mg, and internally at a dose of 6.4 mg.
For the consistent characteristics of preparations, zocrema, preparations, which are varied by different pharmaceutical applications, and to use the same speech in the same dose, vicorist understand "Bioequivalence". Two preparations are respected by bioequivalents, as if the stench may be the same
Bioavailability and fluidity constant of inoculation (characterizes the fluidity of drug intake in systemic blood flow from the injection site). In case of bioequivalent preparations, it is necessary to ensure the same safety to reach the maximum concentration of speech in the blood.
The oral route of administration, as such is sublingual, may be superior to parenteral routes of administration, and the most simple and most convenient for the sick, without compromising the sterility of preparations and specially trained personnel. However, in the middle you can enter only those speeches, which do not collapse into the intestinal tract, moreover, the lipophilicity of the LH is poured onto the steps of the inoculation. Before the shortest route of introduction, it is also possible to add the staleness of the soaking of the medicinal speeches in the form of the mucous membrane and intestinal motility in the pH of the middle and the warehouse in the intestines, the zocrema in the interdependence of the components of both and other L V. Significant shortfall є also those who are rich L V often collapse during the first passage through the liver.
In addition, the LH itself can contribute to the process of etching and soaking up food speeches, including the acquisition of vitamins. So, for example, osmotic transport facilitates the soaking of the phlegm from the intestines, and antacid agents, neutralizing the hydrochloric acid of the slunk juice, disrupt the process of overdosing of the proteins.
The oral route of administration is sometimes simply not available for some ailments (in case of a sickly face, with a broken act of forging, nauseous vomit, in an unfamiliar age, in an early child). In these cases, medicinal products can be introduced with a thin tube probe through the nose or through the mouth into the tube and/or the duodenum.
Rectal infusion. The introduction of medicinal products in rectum(Rectally) vikoristovuetsya in quiet depressions, if the oral route of introduction is impossibly (for example, during vomiting) or the medicinal speech may have an unacceptable taste and smell and collapse into the sac and upper intestinal tract. Even more often the rectal route of introduction is victorious in pediatric practice.
Rectally medicinal speeches are administered in the form of suppositories in the form of medicinal enemas with a total volume of 50 ml. With the introduction of speeches in such a way, which tease the mucous membrane of the rectum, they are mixed in front with mucus and warmed up to body temperature for a quick soak.
From the rectum of the medicinal speech, it is swept up and comes up to the deep blood circulation, 50% bypassing the liver. The rectal passage is not vicorated for the introduction of high-molecular medicinal speeches of a protein, fatty and polysaccharide structure; Rectal injections of speech are administered rectally for a mass injection on the mucous membrane of the rectum, for example, suppositories with benzocaine (anesthesin).
B. Parenteral routes of administration
Before parenteral routes, the introduction is seen:
internal;
internal arterial;
intrasternal;
internal language;
subskirny;
intracerebral;
under the shell of the brain; and others.
At the vein, inject waters of medicinal speeches. The introduction of a large number of medicinal speeches into the vein should be carried out regularly (often after a forward dilution of the drug with sodium chloride or glucose).
However, as it is necessary to create a high concentration of medicinal speech in the blood, it is necessary to inject it quickly, in a jet. Internally, the introduction of great expansions is carried out in a drip (infusion) way. In such cases, there are special systems with urticaria, which allow you to adjust the speed of the introduction. The rest of the time is to make 20-60 drops per min, which is approximately 1-3 ml.
In small numbers, it is possible to administer intravenously hypertonic solutions (for example, 10-20 ml of 40% glucose solution). Through the risk of blockage of the vessels (embolism), it is unacceptable to introduce internally oil solutions, suspensions, water solutions from gas bulbs. Introduction at the vein of drugs with an irritating effect can lead to the development of thrombosis.
The internal path of introduction sounds victorious when given an indispensable medical assistance, or it can be scheduled and for course examination in the minds of a hospital and outpatient.
Intra-arterial introduction. The introduction of the medicinal speech into the artery, which secures the singing organ, makes it possible to create a concentration of strong speech in the new temple. Intra-arterial injection of radiopaque and antitumor preparations. In some cases, antibiotics should be administered intra-arterially.
Intrasternal insertion (Introduction into the sternum). This way of introducing vicorist is in case of impossibility of internal introduction, for example, in children, especially of a frail age.
Internal language introduction. Let’s start introducing medicinal speeches at the upper level of the countryside of sydnichny m'yaz. Internally introduce both lipophilic and hydrophilic medicinal speeches. The soaking of hydrophilic L with intravenous administration is carried out in the main way of filtration through intercellular spaces in the endothelium of vessels of skeletal malignancies. Lipophilic drugs are wetted by the roofs in a way of passive diffusion. M'yazova tissue can be good blood-draining and to that the soaking up of medicinal speeches in the blood must be done quickly, which allows after 5-10 minutes of creation to reach a high concentration of medicinal speech in the blood.
internally inject water drops (up to 10 ml), and for a safer effect - oily drops and suspensions, which will stop the soaking of speech from the place of introduction into the blood (Fig. 1.5). Internally, it is impossible to introduce hypertonic differences and dramatic speech.
Pidshkirne introduction. With the introduction of the skin, the liquoric speech (lipophilic and hydrophilic) is soaked in the same ways (in a way of passive diffusion and filtration), as with the intravenous injection. However, from the subshkyrnoy cellular tissue of the medical speech, it is more likely to be wetted, lower from the m'yazovoj tissue, shards of hemorrhage of the pidshkirnoy cellular tissue are less intense, lower hemorrhage of the bone m'yazy c.
It is important to introduce water and oil mixtures and suspensions (div. Fig. 1.5). Silicone containers are implanted in the cell wall; tablets are sterile solid medicinal forms and are implanted in the interscapular region. Podshkirno it is impossible to introduce speech with teasing and hypertonic differences.
Vnutrishnyorevne introduction. Speech should be injected at the empty line between parietal and visceral leaves. This way is vikoristovuetsya, for example, for the introduction of antibiotics under the hour of operations on the empty stomach.
Introduction to the lining of the brain. Medical speech can be administered subarachnoidally or subdurally. In this rank, with infectious lesions of tissues і the tunics of the brain to inject antibiotics, as if it is rotten to penetrate through the blood-brain barrier. Subarachnoid distant administration of macular anesthetics vicorist for spinal anesthesia.
Internally, intraarterially, intrasternally, internally, intrasternally, intrasternally, and intramuscularly, the introduction of the lining of the brain requires sterile medicinal forms and is required by qualified medical personnel.
Inhalation introduction (Vid lat. inhalare - Breathe in). Inhalation inject gas-like speech, steamed speech, which is easy to evaporate, aerosols and powdered suspensions of finely dispersed solid speech. The soaking of medicinal speeches at the blood from the great surface of the legenium is felt very quickly. In this order, introduce bones for inhalation anesthesia.
Inhalation introduction (sound at the sight of aerosols) vicorist is also for infusion on the mucous membrane and smooth m'yazi of the deep paths. This is one of the most wide-spread methods of introducing bronchorosis and glucocorticoid preparations in bronchial asthma. In this way, wetting of speeches at the blood is unbearable, shards are produced before the appearance of systemic side effects.
Intranasal administration. Speech should be injected near the empty nose at the sight of streaks or special intranasal sprays. Soaking up comes from the mucous membrane of the empty nose. In such a way to administer preparations of certain peptide hormones, which are prescribed in small doses. For example, desmopressin, an analogue of the antidiuretic hormone of the posterior part of the hypophysis, is administered intranasally in non-civil diabetes at a dose of 10-20 mcg.
Transdermal entry. Deyakі lipophilic medicinal speech in the form of dosing ointments or plastir (transdermal therapeutic systems) is applied to the skin, soaked from the surface in the blood (when the speech is taken from the systemic blood flow, bypassing the liver) and may resorptive action. In the rest of the hour, this way will be victorious for the introduction of nitroglycerin. For the help of transdermal medicinal forms, it is possible to increase the permanent therapeutic concentration of the medicinal speech in the blood and in this way to secure the trivaly juicy effect. So, plasters, which vengeance of nitroglycerin, can cause antianginal disease (a juicy effect in angina pectoris) for 12 years.
It is possible to introduce ionized medicinal speeches for additional iono-phoresis (ionophoretic introduction). When such speeches are soaked, after they are applied to the skin, the mucous membranes are blown under the influx of a weak electric field.
In addition, medicinal speeches are applied to the skin or mucous membranes for obsession with women. In such types of vicarious, there are special medicinal forms for good zastosuvanya (ointments, creams, rosiny for zovnishny zastosuvannya). When tsimu vmoktuvannya LH at the blood є nebazhanim.
The medicinal speech can also be injected into the empty pleura (anti-tuberculosis infections), into the empty bursa (introduction of hydrocortisone in rheumatoid arthritis), into the body and into the lumen of the organ (for example, the introduction of oxytin into the cervix and body of the uterus for tech).
^ 1.2. ROZPODIL LIKARSKY SPEECHES INTO ORGANIZMS
After entry into the systemic bloodstream, LVs are distributed in different organs and tissues. The nature of the distribution of LVs is rich in why it is determined by their differences in water or lipids (that is, their permeable hydrophilicity or lipophilicity), as well as the intensity of regional blood flow.
Polar hydrophilic speech is divided unevenly in the organism. Most of the hydrophilic drugs do not penetrate the cells and are distributed mainly in blood plasma and interstitial media. In the interstitial homeland, the stench is consumed through the interstitial spaces of the endothelium of the vessels. In the endothelium of the capillaries of the brain, the intercellular spaces of the day - endothelial cells are closely adjacent one to one (between the cells are the so-called space contacts). Such an uninterrupted ball of endothelial cells fills the blood-brain barrier (HEB), which transcends the subdivision of hydrophilic polar speeches (including ionized molecules) in the tissue of the brain (div. Fig. 1.3). To sing the bar'ern function vykonuyut, maybe, clitiny glії. Through this bar, not a lot of hydrophilic drugs (for example, levodopa) penetrate only for the help of active transport.
However, there are brain cells, which are not protected by the blood-brain barrier. The trigger zone of the vomitus center is accessible to certain receptors that do not penetrate the blood-brain barrier, such as the dopamine receptor antagonist domperidone. Tse allows vikoristovuvaty domperidone as an anti-diarrheal drug, which does not spill into other structures of the brain. In addition, when the meninges are inflamed, the hematoencephalic barrier becomes more penetrable for hydrophilic drugs (it allows you to administer intravenously sodium strength benzylpenicillin for the treatment of bacterial meningitis).
Crim hematoencephalic bar'єrіv, in organisms - other histogematic bar'єri (tobto bar'єri, sho vodokremlyuyut krov vіd fabrics), yakі є pereskodoyu for rozpodіlu hydrophilic drugs. that placental bar'eri. Placental barrier under the hour of vagity pereskodzhaє penetration of some polar hydrophilic drugs from the mother's body into the fetus's body.
They are equally divided in organisms by lipophilic non-polar speech. The stinks penetrate through the path of passive diffusion through the membranes of the clitin and rozpodіlyayutsya both in the post-clitin, and in the internal clitin organism. Lipophilic drugs pass through the mustache of histohematic barriers, zocrema, diffuse without mediation through the membranes of the endothelial cells of the capillaries near the brain tissue. Lipophilic drugs easily pass through the placental barrier. A lot of medical reasons can put pressure on an unsatisfactory diet, and that the intake of drugs by pregnant women is to be blamed for the suvorim control.
Injection into the PV rozpodil also gives the intensity of blood supply to the organs and tissues. The lyric speeches are more widely spread in the organs, which are well perfused, that is. Organs with intensive bleeding, such as the heart, liver, nirka, and milking properly - in tissue with viable filthy bleeding - subcutaneous tissue, fatty and cystic tissue.
^ 1.3. DEPOSIT OF LIKAR SPEECHES IN ORGANIZATIONS
D When rozpodіlі in the body deakі L often can zatrimuvatsya and accumulate in different tissues. It seems to be mainly due to the reversible linkage of LH with proteins, phospholipids and nucleoproteins clitin. This process is called deposition. The concentration of speech in the region of deposition (depot) can be high. From the depot, the speech gradually vibrates in the blood and spreads through other organs and tissues, including its reachable areas. The deposition can be carried out until the extension (prolongation) of the drug or the effect of the last. This is how it is observed during the introduction of an intravenous anesthesia - thiopental-sodium, high-grade disease, as it accumulates in fatty tissue. The drug causes a non-trivial anesthesia (about 15 minutes), after the initiation of such an anesthetic sleep (lasting 2-3 years), the application of thiopental to the depot.
The deposition of LH in certain tissues can lead to the development of side effects. For example, tetracyclines bind to calcium and accumulate in the bone tissue. With this stink, they can disrupt the development of the skeleton in children. Z cієї causes qi preparations and not guilty are recognized by vaginal women.
Bagato L binds with blood plasma proteins. Weakly acidic compounds (non-steroic antiseizure agents, sulfanilamides) are mainly associated with albumins (the largest fraction of plasma proteins), and weak bases are associated with α1-acidic glycoprotein and other plasma proteins blood. Linking drugs with plasma proteins is a reverse process, which can be presented as an upcoming rank:
LV+protein complex LV-protein.
Complexes of speech - protein do not penetrate through the membranes of the clitin and through the intercellular gaps in the endothelium of the vessels (the stench is not filtered and in the capillaries of the nirk glomeruli) and to that it is its own reservoir or depot of this speech in the blood.
When combined with LH proteins, they do not show pharmacological activity. Ale oscilki tse zv'yazuvannya є werewolves, part of the speech is constantly vilable from the complex with the protein (it occurs with a reduced concentration of the free speech in the blood plasma) and may pharmacological effect.
Contact with blood plasma proteins is not specific. Various drugs can bind with one and the same proteins with a high affinity, with which stinks compete for the place of binding on protein molecules and can bind one to one. At what great value can the degree of binding of speech from proteins at their therapeutic concentrations in the blood. So, the same, Tolbutamid (Gipoglikemiychna Zasib, stalling at the Tsugronoy DIABETI) is approximately 96% of the plasmi blood (at the same time, and the foot, in the active station, is known in the blood near 5% of the rushovini). With one-hour recognition of sulfanamides, yakі in therapeutic concentrations are associated with a significant fraction of plasma proteins, swidky tolbutamide appears to be associated with the disease. It is necessary to produce to increase the concentration of free tolbutamide tfc blood. The result, as a rule, is supra-world hypoglycemic effect to the drug, as well as to the effect of the scourge, the biotransformation and excretion of the organism is not associated with speech proteins. Of particular concern is the immediate recognition of sulfanamides and the anticoagulant warfarin, which binds to plasma proteins by 99%. Shvidke increase in the concentration of free warfarin (a drug with a low therapeutic range) to lead to a sharp decrease in blood pharynx and bleeding.
^ 1.4. BIOTRANSFORMATION OF LIKAR SPEECHES
Biotransformation (metabolism)- Changing the chemical structure of medicinal speeches and their physical and chemical powers under the action of enzymes in the body. The main directing of this process is the transformation of lі-pophilic speeches, which are easily reabsorbed in the nirkov tubules, hydrophilic polar streaks, yakі svidko nirki (not reabsorbed in the nirkov tubules). In the process of biotransformation, there is a decrease in the activity (toxicity) of the external speeches.
Biotransformation of lipophilic drugs is mainly due to the influx of liver enzymes localized at the membrane of the endoplasmic reticulum of hepatocytes. Qi enzymes are called microsomal, because
The stinks are associated with other subclitinous fragments of the smooth endoplasmic reticulum (microsomes), which are absorbed during the homogenization of liver tissue or tissues of other organs and can be seen by centrifugation (settled in the so-called "microsomal "fractions").
In blood plasma, as well as in the liver, intestines, legs, skin, mucous membranes and other tissues, non-crosomal enzymes localized in the cytosol or mitochondria. Qi enzymes can take part in the metabolism of hydrophilic speeches.
There are two main types of metabolism of medicinal speeches:
non-synthetic reactions (metabolic transformation);
synthetic reactions (conjugation).
Metabolic transformations include such reactions: oxidation, reduction, hydrolysis. A lot of lipophilic spores are oxidized in the liver under the influence of the microsomal system of enzymes that act as oxidases of disturbing functions, or monooxygenases. The main components of this system are cytochrome P-450-reductase and cytochrome P-450 - a hemoprotein that binds the molecules of the medicinal speech and the acid to its active center. The reaction proceeds with the participation of NADPH. As a result, one acid atom is added to the substrate (medicine speech) from the dissolved hydroxyl group (hydroxide reaction).
RH + 0 2 + NADPH + H + -> ROH + H 2 0 + NADP +, de RH is a medicinal speech, and ROH is a metabolite.
Oxidases of mixed functions may have low substrate specificity. There are many isoforms of cytochrome P-450 (Cytochrome P-450, CYP), which can be metabolized by the skin with a decile of medicinal speech. Thus, the iso-form of CYP2C9 takes part in the metabolism of warfarin, phenytoin, ibuprofen, CYP2D6 metabolizes imipramin, haloperidol, propranolol, and CYP3A4 - carbamazepine, cyclosporine, erythromycin, nifedipine, verapam. Oxidation of certain medicinal speeches occurs under the influx of non-crosomal enzymes, being localized in the cytosol or mitochondria. These enzymes are characterized by substrate specificity, for example, monoamine oxidase A metabolizes norepinephrine, adrenaline, serotonin, alcohol dehydrogenase metabolizes ethyl alcohol to acetaldehyde.
Recognition of medicinal speeches may be due to the participation of microsomal (chloramphenicol) and non-crosomal enzymes (chloral hydrate, naloxone).
Hydrolysis of medicinal speeches is mainly effected by non-crosomal enzymes (esterases, amidases, phosphatases) in blood plasma and tissues. At the same time, the introduction of water leads to the development of ethereal, amide and phosphate bonds in the molecules of medicinal speeches. Hydrolysis is accompanied by folded ethers - acetylcholine, suxamethonium (hydrolyzed with the participation of cholinesterases), amides (procainemid), acetylsalicylic acid (div. Table 1.1).
Table 1.1. The main ways of metabolism (biotransformation) of medicinal speeches
| Processes Biotransformation fermenti
| Chemical reactions | Likarsky speeches |
Metabolic reactions
| Oxidation Hydroxylase Demethylase N-oxidase S-oxidase
| Hydroxyluvannya Deaming N-oxidation S-oxidation | Phenobarbital, codeine, cyclosporine, phenytoine, propranolol, warfarin. Diazepam, amphetamine, ephedrine. Morphine, quinidine, acetaminophen. Phenothiazines, omeprazole, cimetidine |
| Reinvention reductase
| Reinvention | Chloral hydrate, metronidazole, nitrofuranium |
| Hydrolysis Esterazi Amidazi
| Hydrolysis of collapsible ethers Hydrolysis of amides | Procaine, acetylsalicylic acid, enalapril, cocaine. Novocainamide, lidocaine, indomethacin |
Biosynthetic reactions
| ^ Conjugation from excess sulfuric acid | ||
| Sulfotransferase | OSvita sulfates | Acetaminophen, steroids, methyldopa, estrone |
| ^ Conjugation from excess glucuronic acid |
||
| Glyukuroniltransf-raz | Utvorennya efiriv, thio-efiriv or glucuronic acid amides | Acetaminophen, chloramphenicol, diazepam, morphine, digoxin |
| ^ Conjugation with excess a-amino acids (Glycycin, glutamine) | Amіduvannya | Nicotinic acid, salicylic acid |
| methylation |
||
| Methyltransferase | Arrival of a metal band | Dopamine, epinephrine, histamine |
| acetylunation |
||
| N-acetyl transfer | Utvorennya amides of octic acid | Sulfanamide, isoniazid |
Metabolites, which are utvoryuyuyutsya as a result of non-synthetic reactions, may be more high activity in other periods of the mother, lower in the middle of the day. The butt of the promotion of the activity of medicinal speeches in the process of metabolism is the achievement of the successors of the licks (prolics). Prolics are pharmacologically inactive, but in the body the stench transforms into active speech. For example, salazopiridazine, a drug for the treatment of nonspecific virazic colitis, is converted to sulfapiridazine and 5-aminosalicylic acid by the intestinal azoreductase enzyme
An acid that can be antibacterial and antiseptic. A lot of antihypertensive effects, for example, an inhibitor of angiotensin-converting enzyme (enalapril), are hydrolyzed in the organisms of active diseases. Prophets make a number of advances. Most often, with the help, problems arise with the delivery of medicinal speech to the month of yoga. For example, levodopa acts as a precursor to dopamine, but it does not penetrate through the blood-brain barrier in the central nervous system, but DOPA-decarboxylase transforms into active speech - dopamine.
Some of the products of metabolic transformation are toxic, lower in half. Thus, the toxic effects of preparations that can be mitigated by nitrogroups (metronidazole, nitrofurantoin) are due to the intermediate products of the metabolic elimination of NO 2 -rpynn.
In the process of biosynthetic reactions (conjugation) to the functional grouping of molecules of medicinal speeches or their metabolites, there is an excess of endogenous compounds (glucuronic acid, glutathione, glycine, sulfate and in.) or high polarity imichnі groups (acetyl, methyl groups). These reactions proceed with the participation of enzymes (most importantly transferases) of the liver, as well as enzymes of other tissues (lungs, nirk). Enzymes are localized in microsomes or in the cytosolic fraction (div. Table 1.1).
The most significant reaction is conjugation with glucuronic acid. The addition of excess glucuronic acid (glucuronide elimination) is due to the participation of the microsomal enzyme UDP-glucuronyltransferase, which has a low substrate specificity, due to which even rich in medicinal speeches (as well as to exogenous conditions, such as corticosteroids and bilirubin); . In the process of conjugation, high-polarity hydrophilic slugs are established, which are easily produced by nirks (a lot of metabolites are also conjugated). Conjugates, as a rule, are less active and toxic, lower in medicinal speech.
Shvidkіst biotransformatsії lіkarskih rechovina to lay rich chinnikіv. Zocrema, the activity of enzymes that metabolize medicinal speeches, deposited in state, vіku, I will become an organism, one-hour recognition of other medicinal properties. In humans, the activity of microsomal enzymes is higher, while in women, the synthesis of these enzymes is stimulated by human hormones. For this reason, speech is metabolized more in men, less in women.
In the embryonic period, the number of enzymes in the metabolism of medicinal speeches is greater, in newborns in the first month of life, the activity of these enzymes is reduced and reaches a sufficient level only after 1-6 months. Therefore, in the future, it is not recommended to use such drugs as chloramphenicol (due to insufficient enzyme activity in the upregulation of the process of yogo conjugation and toxic effects).
The activity of liver enzymes decreases in the elderly, after which the metabolic rate of the rich drug speeches changes (in persons over 60 years of age, such drugs are prescribed at lower doses). When the liver becomes ill, the activity of microsomal enzymes decreases, the biotransformation of certain medicinal speeches increases, and there is an increase in the severity of depression. In the languor of those weakened ailments, the sneshkodzhennya of medical speeches is more pronounced.
Under the influx of some medicinal drugs (phenobarbital, rifampicin, carbamazepine, griseofulvin), there may be an induction (increased synthesis) of microsomal enzymes in the liver. As a result, with one-hour recognition of microsomal enzyme inducers and other drugs (for example, glucocorticoids, oral contraceptives), the rate of metabolism of the remaining ones increases and decreases. In some cases, the metabolic rate of the inductor itself may be increased, resulting in a change in pharmacological effects (carbamazepine).
Active drugs (cimetidine, chloramphenicol, ketoconazole, ethanol) reduce the activity of metabolizing enzymes. For example, cimetidine, a microsomal oxidation inhibitor that enhances the metabolism of warfarin, may induce an anticoagulant effect and provoke bleeding. Vodomin speech (furanocoumarin), which is found in grapefruit juice, ignites the metabolism of such medicinal speech, like cyclosporine, midazol, alprazol and, also, help their effect. In case of one-hour stasis of medicinal speeches with inducers or metabolic inhibitors, it is necessary to adjust the doses of these speeches.
The rate of metabolism of some medicinal speeches depends on genetic factors. Appearing a division of pharmacology pharmacogenetics, one of the leading causes of pathology of enzymes in drug metabolism. p align="justify"> Changes in the activity of enzymes often result in a mutation of a gene that controls the synthesis of this enzyme. Damage to the structure and function of the enzyme is called enzymopathy (fermentopathy). In case of enzymopathies, the activity of the enzyme can be increased, and in the course of the process of metabolism of drug speeches, it may also decrease. On the other hand, the activity of enzymes may be reduced, due to which the destruction of medicinal speeches may be more pronounced and may be more pronounced until the appearance of toxic effects. Peculiarities of different medicinal speeches in individuals due to genetically altered enzyme activity are shown in Table. 1.2.
Table 1.2. Particular reactions of the organism to medicinal speech in case of genetic deficiency of these enzymes
| Enzyme deficiency | Special reactions | Likarsky speeches | Population expansion |
| Glucose-6-phosphate dehydrogenase of erythrocytes | Hemolysis of erythrocytes after the adoption of quinone. Hemolytic anemia | Quinine, quinidine, sulfanamide, acetylsalicylic acid, chloramphenicol | Tropical and subtropical lands; up to 100 million osib |
| Liver N-acetyltransferase | Partial side reactions through more acetylation of speeches | Isoniazid, sulfanamide, procaynamide | European (up to 50%) |
| Catalase | Revealing the effect through more atomic acidification | water peroxide | Japan, Switzerland (up to 1%) |
| Pseudocholinesterase in blood plasma | Trival relaxation of skeletal masses (6-8 years, 5-7 years of age) through more hydrolysis of speech | Succinylcholine (ditilin) | Europeans (0.04%), Eskimos (1%) |
^ 1.5. VIVEDENNYA LIKAR SPEECH FOR THE ORGANISM
Drug speech and their metabolites are excreted (excreted) from the body mainly from the main section (nirkov excretion), as well as from the stomach in the intestinal lumen.
Nir's excretion. Treatment of drug speech and their metabolites with nirkami is associated with the participation of three main processes: glomerular filtration, active secretion in the proximal tubules and tubular reabsorption.
Glomerular filtration. The medicinal speech, differentiated in the blood plasma (behind the vein of the speech, bound with plasma proteins and high molecular weight layers), is filtered under a hydrostatic vice through the intercellular gaps in the endothelium of the capillaries of the nirk glomeruli and enlightenment of the tubules. As much as speech is not reabsorbed in the nirk's tubules, the stench is expelled from the cut.
Active secretion The pathway of active secretion in the lumen of the tubules shows more speech, excreted by nirks. Speech is secreted in the proximal tubules behind the help of special transport systems against the concentration of the gradient (this process increases energy). Іsnuyu okremі transport systems for organic acids (penicilin, salicylates, sulfanilamides, thiazide diuretics, furosemide and іn.) and organic bases (morphine, quinine, dopamine, serotonin, amіloride and a number of other speeches). In the process of vision, organic acids (also like organic bases) can competitively remove one of the bonds with transport proteins, after which the excretion of speech, which is observed, decreases.
Reabsorption (recovery). Through the membranes of the Nirkovian tubules, the speech is reabsorbed by a path of passive diffusion following a concentration gradient. In this way, non-polar lipophilic slugs are reabsorbed, since stinks easily penetrate through the membranes of the epithelial cells of the nirk tubules. Hydrophilic polar speech (including ionized spores) is practically not reabsorbed and excreted from the body. In this manner, the introduction of weak acids and weak bases in direct proportion to the level of their ionization and, therefore, a significant world to lie in the pH of the section.
/Acid reaction section with the excretion of weak bases (for example, alkaloids in nicotine, atropine, quinine) and aggravating the appearance of weak acids (barbiturates, acetylsalicylic acid). To speed up the identification of weak foundations by nirkami, change the reaction of the section V acid side (change pH section). Call at times to prescribe ammonium chloride. And yet, as it is necessary to promote the excretion of weak acids, prescribe sodium bicarbonate and in other cases, to destroy the reaction of the cross section in the puddle side (push the pH of the cross section). Intravenous administration of sodium bicarbonate, zocrema, vicorist for accelerated withdrawal of barbiturates or acetylsalicylic acid in various overdoses.
Reabsorption of certain endogenous rhechovins (amino acids, glucose, secic acid) is affected by active transport.
Vision through the duct-intestinal tract. A lot of drugs (digoxin, tetracyclines, penicillins, rifampicin and others) are seen in the intestinal lumen (invariably, or in the presence of metabolites and conjugates) and are often excreted in the body with excrement. However, part of the speech can be re-moistened and when passing through the liver again
Seen from zhovchyu at the lumen of the intestines thinly. This cyclical process is called enterohepatic (intestinal-hepatic) circulation The agents of speech (morphine, chloramphenicol) are seen in the presence of conjugates with glucuronic acid (glucuronides), which are hydrolyzed in the intestines to form active speeches, thus reabsorbing again. In this way, enterohepatic circulation spryaє prolongation of diuretic speeches. Deyakі likarsky speech rotten somktuyutsya іz slunkovo-intestinal tract and vyvodya z organism through the intestines. Such speeches are important to stop for treatment or prevention of intestinal infections and dysbacteriosis (neomycin, nystatin).
Gas-like and summer speech are seen as light. Such a way to produce bones for inhalation anesthesia. Active speech can be seen as sweat, sloughs (penicillins, iodides), sloughs of the intestines (quinine) and intestines (weak organic acids), mucus sloughs (rі-fampicin), lactiferous sloughs during lactation (snodiyny sloughs, ethyl alcohol, nicotine). in .) .). At the beginning of the year, the medicinal speech, which is seen as milk stings, can be drunk at once from milk to the body of a child. For those mothers who are pregnant, it is contraindicated to take medications (cytostatics, narcotic analgesics, chloramphenicol, isoniazid, diazepam, antithyroid drugs, etc.) on a child.
To characterize the pregnancy processes, in which active drug speech is seen from the body, the understanding is introduced elimination, yake going through two processes: biotransformation and vivendennia. Some of the elimination process is characterized by low pharmacokinetic parameters (div. division "Mathematical modeling of pharmacokinetic processes").
^ 1.6. MATHEMATICAL MODELING OF PHARMACOKINETIC PROCESSES
The magnitude of this pharmacological effect is rich in what is determined by the concentration of medicinal speech (LV) in these organs or tissues, devastating its effect. Therefore, it is important to maintain a positive (therapeutic) concentration of LH in the area of yoga. However,
more fluctuations in the concentration of speech in the tissues is practical
impossibly, in case of pharmacokinetic studies, a con
centralization of LV in blood plasma, yak for more speeches correlate with
their concentrations in target organs.
As a result of inoculation, distribution, deposition and elimination (biotransformation and removal) of the drug concentration in blood plasma changes. Qi change can be represented graphically. For the first concentration of the drug speech, the blood plasma will decrease immediately and after a few intervals, an hour after the first injection, and on the basis of the withdrawal of data, there will be a curve of change in the concentration of LH in the hour, or so the pharmacokinetic curve is called (Fig. 1.6).
In order to assess the impact of the process of smoking, analyze the deposition of that elimination on the concentration of LH in the blood, vicoryize mathematical pharmacokinetic models. One-chamber, two-chamber and multi-chamber pharmacokinetic models are distinguished.
Hour
internal introduction
introduction inside (per os)
In a single-chamber model, the body is mentally served at the sight of a chamber filled with motherland. Speech can go into the chamber step by step, as with the insertion in the middle (or other paths of the introduction), or mittevo, like with a swedish internal insertion (Fig. 1.7).
After the presence of speech in the chamber in a quantity D, it will rise mittevoly and evenly and occupy the volume of the chamber, at which concentration of speech, as it is created in the chamber, it is indicated as a cob concentration - 0. The volume of speech under the camera is V d (volume of distribution) = D/C 0 .
Clinical practice has a victorious parameter, which takes away the name zadaetsya obsyag rozpodіlu(apparent volume of distribution, V d).
It is possible to understand the distribution - a hypothetical understanding of the motherland of the organism, in which the medical speech is divided equally and when it is in the concentration, which is the concentration of this speech in the blood plasma (C). Apparently, the volume of rozpodіlu that is given, V d \u003d Q / C de Q - the amount of speech in the body at a concentration in blood plasma C.
Assuming that the speech after intravenous administration at a dose of D was uniformly and evenly distributed in the body, then it was subdivided into V d = D / C 0, de Z 0 - the concentration of the speech in the blood plasma.
Obsjag rozpodіlu, scho daєtsya, allowing to judge about those in which spіvvіdnoshnіnі rozpodіljaєy razpodіlієє speech іzh rіdinami organism (blood plasma, interstitial, vnutrіshnoklіtinnoї rіdinami). So, even though the value of V d, whether or not speech, can be approximately 3 liters (average plasma volume
blood), which means that speech is important to be found in blood plasma. Such obsyag is typical for large molecular scales, as it practically does not penetrate the blood cells through the endothelial vessel (do not go beyond the intervessel bed), for example, for heparin (V d - close to 4 l).
Even Vd is equal to 15 l (total mean volumes of plasma and interstitial rіdina), speech is important to be found in the blood plasma and interstitial rіdini (in the interstitial rіdinі), tobto. does not penetrate the middle of the clitin. Imovirno, tse hydrophilic layer, so as not to pass through the clitin membrane. These speeches are preceded by aminoglycoside antibiotics (gentamicin, tobramycin). That is why it is not enough to add antibiotics to microorganism, because it is the middle clitin, tobto. ineffective against internal clitinal infections.
Deyakі likarsky speeches may have a volume of about 40 l (the average volume of all the rіdin organism). Tse means that the stench is rebuying like in the post-clitin, and in the internal clitin homelands of the body, tobto. penetrate through clitin membranes. Basically, lipo-philic non-polar sexes are divided in this way in organisms.
As a result, the value of V d of the medicinal speech significantly exceeds the total body volume, while the speech was more deposited in the peripheral tissues, and the concentration in the plasma is supraorbitally low. The great significance of this difference is typical for the tricyclic antidepressants imipramine and amitriptyline (V d - about 1600 l). Such L cannot be effectively removed from the body for additional hemodialysis.
After the equal distribution of speech in the volume of the chamber and reaching the concentration 0, the concentration of speech in the chamber gradually decreases due to the participation of two processes - biotransformation and excretion (div. Fig. 1.7). Offenses and processes are combined by the term elimination.
The greater number of likarsky speeches is sparsely eliminatsiy to fall in the concentration of speech (the less concentration of speech, the lesser the swidkist eliminatsiy). In this case, the curve of change in the concentration of speech in the hour may have an exponential character (Fig. 1.8). Such elimination of the kinetics of the 1st order (at the same time is eliminated pevna part speech ^.
The main parameters that characterize the process of elimination, є constant of dryness of elimination(k el , k e) period of writing(T 1/2).
48
The constant of the frequency of elimination of the 1st order shows how part of the speech is eliminated from the body in one hour (distance min -1, year -1). For example, as if speech were administered intravenously at a dose of 100 mg, it became 0.1 year ~", then after 1 year the amount of speech in the blood was 90 mg, and after 2 years - 81 mg, etc.
Not a lot of drugs (etanol, phenytoin) are eliminated in a similar way to zero-order kinetics. The density of such elimination is to be found in the concentration of speech and є constant value, tobto. eliminuetsya at the same time pevnu kіlkіst speech (for example, 10 g of pure ethanol is eliminated in 1 year). It is due to the fact that at therapeutic concentrations of the names of the speeches in the blood, there is an abundance of enzymes that metabolize the speeches. Because of the increased concentration of such speeches in the blood, there is no evidence of their elimination.
The period of application (t I / 2, half-life) is an hour, during which the concentration of speech in plasma decreases by 50% (Fig. 1.9). For greater LH (for quiet, elimination of such suborders of kinetics of the 1st order), the period of napіvelіmіnatsії - the value of the postion at the singing boundaries and do not lie in the dose of LH. To that, while in one period of administration 50% of intravenously administered LH is seen in blood plasma, then in 2 periods - 75%, and in 3.3 periods - 90% them for support її postіynoї concentration in the blood).
The period of application of the application due to the constant fastness of elimination of the onset of spontaneity:
T 1/2 \u003d ln2 / k eI \u003d 0.693 / k el.
As soon as the intravenous introduction of speech is carried out, the concentration of speech in the plasma is measured after short intervals of an hour, then it is possible to eliminate the two-phase nature of the change in the concentration of speech in the blood (div. Fig. 1.11).
This very nature of the curve can be attributed to an additional two-chamber pharmacokinetic model (Fig. 1.10). In this model, the organism is represented by two cameras that are connected to each other. One of the chambers of this model is called central and represents blood plasma and well perfused organs (heart, liver, nirki, legenia), and another, called peripheral, represents
filthy perfused tissue (shkir, fat, m'yazovu tissue). Speech should be injected near the central chamber, devastated and evenly divided and the stars penetrate into the peripheral chamber. This period is indicated as a phase of a sub-phase, or a phase. Then the speech is redistributed from the peripheral chamber to the central one and is seen from it after elimination. Tsya phase (the elimination phase) is designated as the β-phase. The α-phase is characterized by a parameter, which is called a period of navrozpodіlu - t 1/2 (X, and the characteristic of the β-phase is a wet period of napіvelіmіnatsії, which is indicated as t 1/2 g (Fig. 1.11). ї chambers in the peripheral shvidshe, nizh eliminuetsya.
Clearance is a pharmacokinetic parameter that characterizes the frequency of changes in the body in the form of medicinal speech.
Oscilki zvіlnennya organism vіd lkh vіdbuvaєtsya for rahunok protsessі biotransformatsії (metabolіzmu) і ekkretsії, razraznyayut metabolіchny і ekskretorny clіrens. Metabolic clearance (Cl met) and excretory clearance (C excr) in total add up systemic (solid) clearance (Cl t , total clearance):
Cl met + W excr = Cl t
The systemic clearance is numerically higher than the rate of change that fluctuates in speech in one hour (distance - volume in a single hour, for example, ml / min, l / year, other times with body weight, for example, ml / kg / min):
CL t = V d k el
The value of clearance is directly proportional to the density of the elimination of speech and wrapped in proportion to the concentration in the biological motherland (in blood, blood plasma, serum):
De S - concentration of speech.
Fallow in the ways of eliminating L distinguish nirk clearance (C1 hep), hepatic clearance (Cl hep), as well as clearance, which is affected by other organs (lungs, slings, sweat and milk deposits, post-hepatic metabolism). The most important storage systems for systemic clearance are nirk and hepatic clearance.
Nirk clearance is numerically superior to the amount of blood plasma that fluctuates in HL at one hour and accumulates due to the intensity of glomerular filtration processes, tubular secretion and reabsorption. Nirk clearance can be determined at a constant concentration of speech in plasma:
De C u - the concentration of speech in the section, C - the concentration of speech in the blood plasma V u - the severity of the section.
The hepatic clearance is deposited due to the processes of biotransformation of the drug and the excretion of the unchanged drug from the liver. The significance of nirk and hepatic clearance should be cured when HL is recognized as ill due to a lack of niro or the liver is viable.
^ Optimization of dosing of medicinal speeches
To achieve the optimal therapeutic effect of the drug, it is necessary to constantly increase the therapeutic concentration in the blood. The ruff of speech, which is constantly lit in the blood plasma, is signified as stationary concentration(C ss, 3 steady-state). Stationary concentration is restored when the level of speech is reached by the process of suppuration of speech into the systemic bloodstream and by the process of elimination (if the level of suppuration is equal to the level of elimination). The most simple way to achieve a stationary concentration is intravenously dripping (Fig. 1.12). With intravenous spotted insertion, the value of C ss should lie in the consistency of the insertion of the speech, which can be assigned to the formula D / T \u003d CI.
It is necessary to administer the drug with such a fastness, in order to increase the therapeutic concentration in the blood. Іsnuє range of therapeutic concentrations (Fig. 113). The lower limit of the range is the minimum effective concentration (C ™ p, lower than the concentration of speech does not give the necessary dose), the upper limit is the maximum safe concentration (C ™ is higher than the area of toxic concentrations). Sound up the average concentration of the range, tobto. average therapeutic concentration of speech in the blood. The values of the average therapeutic concentrations of medicinal speeches are found in the prehistoric literature.
The hour to reach the stationary therapeutic concentration of speech in the blood should be deposited during the period of application. Through the period of napіvelіmіnаtsії reach 50%, after 2 periods of nіvіlіmіnаtsії - 75% and after 3.3 period - 90% of the stationary level of speech in the blood. Therefore, if it is necessary to remove a swedish therapeutic effect, especially if speech can take a long period of administration, a large dose of a navantage drug (to reach a stationary therapeutic concentration), and then inject speech fuziyno with singing swidkistyu for the support of stationary concentration. However, most of the speeches are administered in small doses at intervals of one hour (mostly the speeches are administered internally). In such cases, the concentration of speech in the blood is not overstayed, but changes according to the stationary level, and the level of coliation is not responsible for going beyond the range of therapeutic concentrations. Therefore, after the recognition of a navantazhuvalny dose, in order to ensure the attainment of a stationary therapeutic concentration, it is necessary to administer smaller amounts of incremental doses, if necessary, to secure an even small concentration of speech in the blood at any time. ї inpatient therapeutic level (Fig. 1.14). Navantazhuvalno and pіdtrimuyuchu dose LZ for a specific skin disease can be developed according to the formulas, in whichever pharmacokinetic parameters are presented in this division: general distribution, period of administration and in. parameter, yak bioavailability(Part of the administered dose of speech, which invariably reached the systemic circulation).
The bioavailability of speeches in the case of internal administration to fall due to various factors (div. page 33) and is considered to be an offensive rank. Speech is administered to the ailment internally
evenly and vimiryuyut yogo concentration in the blood through the intervening intervals of the hour. From taking these data off, the curve of the change in the concentration of speech in the hour during intravenous administration is observed. Then, to the same ailment, the speech is administered internally in the same dose and the concentration in the blood is determined at intervals of one hour. For the results of the experiment, there will be a curve of change in the concentration of speech in the hour when administered in the middle (Fig. 1.15).
We then vimiryuyut areas under the concentration curve - hour (AUC, Area Under the Curve). The bioavailability of speech is determined by the following formula:
De F - bioavailability (Fraction); AUC - area under the concentration-hour curve (Area Under the Curve).