Dermatologic agents

The skin performs a set of important functions: protective, thermoregulatory, immune, synthetic and sensory; appeal and success in society depend on its state. In therapy of illnesses of a skin use drugs for external and systemic use, an injection of medicines in the center of a lesion and chromo phototherapy.

Drugs are convenient for external use, but have to be used taking into account barrier function of the skin which is carried out mainly by cornual layer of a false skin. The leading role in topical and systemic treatment of skin diseases belongs to glucocorticoids and retinoida. Glucocorticoids prescribe inside in high doses at severe defeats of a skin. By modification of a molecule of Hidrocortizonum more potent drugs which made possible topical treatment of many skin diseases were framed. Highly active retinoida prescribe inside at ordinary acnes and a psoriasis. By means of change of molecular structure of retinoid drugs for external use were received; their role in prophylaxis of malignant neoplasms and a solar geroderma is now studied. At many skin diseases prescribe inside antimalarial and antitumoral agents, immunodepressants, H1 blockers. Widely apply the dosed ultra-violet radiation to treatment of a psoriasis, an itch and a diffuse neurodermite. At the same time ultra-violet radiation serves as the main reason of malignant neoplasms of a skin. To slow down or prevent development of precancerous diseases, a melanoma and carcinoma cutaneum sun-protection agents and therefore it is strongly recommended to use them help. New antimicotic, antiviral and antibacterial drugs significantly dilated possibilities of dermatologists. Analogs of vitamin D, retinoida and ditranol are used for topical treatment of psoriasis.

Article generally consists of the sections devoted to the separate skin diseases and medicines applied to their treatment. In independent sections only glucocorticoids and retinoida as their role in treatment of skin diseases is extremely big are taken out. Other medicines are discussed with those diseases at which they are applied.

Historical information

Sources of drug treatment of skin diseases go back to ancient Middle Eastern cultures. On the Egyptian medical papyruses, in particular, the alopetion and the means for her treatment consisting of equal parts of fats of a lion, hippopotamus, crocodile, goose, snake and mountain goat are mentioned. In India at leprosy applied arsenic, at pediculosis is mix of mercury and sulfur. The paste consisting of sulfate of iron, bile, sulfate of copper, sulfide of arsenic and antimony was used at a scrotum itch. Many other medicines were invented by Greeks during Hippocrates's era and Romans at the time of Tsels (King, 1927).

At the end of the 19th century treatment of skin diseases still strongly differed from today's. So, on the I World congress of dermatologists in Paris (1889) among the most popular methods of treatment of a dermatofitiya of a hairy part of the head the dermabrazia by means of an emery paper with the subsequent processing by corrosive sublimate" was discussed ", and at syphilis it was recommended to use 50% ointment of oleate of mercury and to begin treatment at a secondary stage (Shelley and Shelley, 1992).

However for the last hundred years when the pathogenesis of skin diseases has been studied, the medicinal arsenal of dermatologists has quickly grown. The century axiom according to which effect of substance is defined mainly by his physical characteristics has been disproved, at last; now not less important part is assigned also to chemical structure. If earlier treatment of skin diseases was generally symptomatic, then now, thanks to scientific and technological developments, there were medicines intended for pathogenetic treatment.

Structure and functions of skin

The skin performs a set of different functions, including protective, thermoregulatory, sensory and immune. The skin consists of two parts — a false skin and the derma spreading it. However in practice quite often carry to a skin also a hypodermic fat which anatomically and functionally is closely bound to it.

In an external part a false skin distinguish four types of cells: keratinotsita, melanocytes (pigment cells), Langergans's cells (antigen presenting cells) and Merkel's cells (tactile cells). The false skin is updated due to proliferation of keratinotsit. These cells contain proteins the keratins forming a cytoskeleton. As different layers of a false skin differ in the keratins which are contained in them, the last use as markers. Excess formation of keratin sign of many skin diseases, including a psoriasis and some fish-skin diseases. In process of maturing and a differentiation of keratinotsita are enlarged, flattened and eventually lose cores. A final stage of their differentiation formation of cornual layer of a false skin.

Formation of a cornual layer perhaps, the most important function of a false skin. The cornual layer interferes with loss by an organism of water and to penetration of harmful substances. The device of a cornual layer can be compared to a bricklaying where as bricks serve cornual flakes, and cement mortar intercellular lipids. Cornual flakes contain the same proteins, as keratinotsita of the top layers of a false skin. You can also like - Vitamin B12 cyanocobalamin injection.

Under horn the granular layer lies. Cytoplasm of his cages is filled with bazofilny granules of a keratogialin. Granules contain inactive protein predecessor profilargin. In process of moving of cages to a horn layer occur defosforilirovanie and proteolis a profilagrina therefore he turns in filagrin. The last connects keratin intermediate filament (tonofilament) among themselves with formation of keratin fibrilla (tonofibrill). Subsequently filagrin breaks up to amino acids which go for formation of the substances absorbing ultra-violet radiation and interfering loss of moisture through skin. Cages of a granular layer contain also other proteins predecessors, for example involucrin, loricrin and tsistatin and (ceratolinin). Transglutaminaza, connecting these proteins among themselves by strong cross communications between an e-amino group of a lysine and at - carat -boksilnoy group of glutamic acid, forms a so-called horn envelope — a rigid layer with cytoplasmatic 'the parties of a membrane of cages. Defects filagri-on and transglutamineelements serve as the reason of some ikhtioz.

In cages of a granular layer there are also lamellar granules, or keratinosoma membrane organellas which contain predecessors of intercellular lipids of a horn layer: ptikolipida, glikoproteida and phospholipids. These substances are emitted by ekzotsitoz on border between granular and horn layers and hydrolyzed to tseramid and free fatty acids. Tseramida, fatty acids and cholesterol are and there are intercellular lipids playing an important role in barrier function of a horn layer of epidermis (Jakubovic and Ackerman, 1992).

Features of pharmacokinetics of dermatologic agents

Skin is the biggest member of the body. Its illnesses are unique the availability to diagnostics and treatment, and results of treatment are obvious not only to the doctor, but also the patient. Dermatologic agents can be applied outwardly, systemically or to enter into the lesion center. In some cases, for example at a psoriasis, drug treatment can be combined with chromo phototherapy.

Drugs for external use have many advantages. The most obvious simplicity of putting drug on a skin and estimates of results of treatment. Besides the majority of such drugs almost don't get to a systemic blood stream and, therefore, don't cause serious complications. For the same reason interactions with other medicines are seldom observed. Guarantee of successful treatment a clear understanding of the mechanism of penetration of medicines through a skin.

As the main obstacle serves the cornual layer of a false skin. Overcoming by substance of a cornual layer is the limiting absorption stage. All process of an absorption takes place three main stages: emergence of a concentration gradient of active ingredient a driving force for its entering in a skin; establishment of equilibrium concentration of active ingredient between basis and cornual layer (depends on a distribution coefficient); penetration of active ingredient deep into skins (depends on a diffusion coefficient). Rate of an absorption (more precisely — a diffusive stream) is described by the following equation (Piacquadio and Kligman, 1998):

J = With x K x D/X, (65.1)

where J — a diffusive stream; With — concentration of active ingredient in a basis; To — a distribution coefficient; D — a diffusion coefficient; x — thickness of cornual layer of a false skin.

The absorption of substances through a skin is influenced by humidity and temperature of a skin, age, existence of damages or an occlusive bandage, a body part on which drug is applied. For example, than the skin is moistened better, that is the more waters contains in cornual layer, the quicker there is an absorption. Humidity of a skin can be increased, having limited losses of water by it by means of an occlusive bandage or ointment on a fatty basis. Permeability of a skin is increased at prematurely born (Barker et al., 1987) and at elderly as their skin is thinner. Permeability is higher in those body parts where the cornual layer of a false skin is thin. And at last, penetration of drugs through a skin is facilitated by such substances as dimethylsulfoxide, propylene glycol and urea.

The intact skin represents a formidable barrier to medicines, however damages and diseases of a skin can significantly facilitate or complicate an absorption. The absorption is considerably facilitated after excision of cornual layer of a false skin by an adhesive tape or an adhesive plaster. The reinforced false skin of plaques at a psoriasis, on the contrary, complicates an absorption whereas at itching a dermatitis * drugs can be soaked up very quickly thanks to cracks on a skin. However the strengthened absorption of drugs for external use is fraught with systemic side effects, for example oppression gipotalamo pituitary and adrenal system at treatment by strong glucocorticoids.

Bases

Speed and extent of absorption of medicine through skin depend on many factors. Active ingredients are, as a rule, mixed with form-building substances, or a basis which brings active ingredients into contact with skin. The basis significantly influences absorption and in case of a right choice itself can favorably influence skin. The basis shall be put and be removed easily, shan't cause irritations and spoil appearance. Active ingredient shall remain in a basis in a stable condition and is easy to be released from it. Because of a lack of knowledge of physical and chemical properties of the operating and form-building substances, that is about distribution of active ingredients between a basis and skin, the first medicines for external application had unacceptable bioavailability. Believe that their pharmacokinetics can be improved considerably by replacement of bases (Guin et al., 1993).

The right choice of a basis is very important. In medicines I for external application the basis constitutes the most part of amount and, therefore, significantly influences absorption and efficiency of active ingredient. The choice of a basis and speed of penetration through skin of active ingredient are determined by coefficient of distribution of substance between hydrophobic and hydrophilic phases, molecular mass of substance and its solubility in water. The ions and polar molecules dissolved in water, as a rule, don't get through the intact horn layer of epidermis.

Depending on quantity of components of a basis it is possible to divide into monophase, two-phase and three-phase.

Powders, creams and liquid bases belong to monophase. Powders, for example starch and talc, absorb moisture, reduce friction, have the calming, softening and cooling effect, but badly keep on skin and often roll down in lumps that limits their application. Dosage forms on the basis of powders are called powders. Mazevy bases protect skin. In quality of bases use waterless substances; they are insoluble in water, or fatty (for example, vaseline), and water-soluble (for example, polyethylene glycol). Ointments on a fatty basis protect skin from drying better, than ointments on a water-soluble basis. It is necessary to emphasize that bases in itself don't moisten skin, and limit losses of water by it, that is hold moisture in a horn layer.

The main advantage of liquid bases consists that they quickly evaporate and have the cooling and drying effect. Solutions and lotions represent dosage forms in which active ingredients either are dissolved, or are weighed in a liquid basis. Both those, and others are suitable for drawing for the parts of the body covered with hair. Of a fir-tree contain the liquid dispersive environment and thanks to presence of polymer have an appearance of gelatinous weight. It is possible to tell that gel represents a grid with the microscopic cells filled with liquid. Gels are suitable for the parts of the body covered with hair too, they provide the best penetration of active ingredient, than solutions and lotions. By mixing of powders, creams and liquid bases it is possible to receive two-phase and three-phase bases.

Talkers (liquid foundation plus powder), pastes (powder plus cream basis) and creams (cream basis plus liquid) treat two-phase bases. In talkers (for example, zinc oxide medicines) water evaporates, leaving powder on skin. Talkers have the cooling, mitigating and comforting effect. Pastes happen drying, mitigating and protective. They are applied, for example, to treatment of ulcers and a chronic dermatosis. Creams represent a product of emulsification or oil in water (liquid creams), or waters in oil (dense creams). When drawing on skin of liquid cream water evaporates, leaving a thin film of active ingredient. Evaporation of water renders not only the cooling, but also drying action. Liquid creams contain the preservatives interfering reproduction of bacteria, but capable to cause allergic contact dermatitis. Dense creams contain less water more oil and, therefore, have the mitigating and moistening effect. Can be an example of a three-phase basis cream-paste.

Liposomes and microspheres belong to the latest bases. Liposomes represent the vesicles from phospholipids weighed in the water environment; they facilitate penetration of active ingredient through skin and improve a ratio between advantage and risk of treatment. Liposomes especially easily get through the damaged sites of skin (Korting et al., 1991). Release of active ingredient happens in two stages. For some time after drawing on skin medicine keeps liquid state and is soaked up slowly, then dries up, merges with skin fat and gets into a horn layer. Microspheres are the polymeric particles of the microscopic size containing active ingredient. Microspheres provide the dosed release of the last and, apparently, have smaller irritant action.

Interchangeability of medicines for external application

Quite often instead of the medicines protected by trademark appoint their cheaper unlicensed analogs. However these two types of medicines aren't always interchangeable. Serve as criteria of interchangeability pharmaceutical equivalence is availability in both medicines of the same active ingredient; bioequivalence is identical bioavailability of active ingredient in two different medicines; therapeutic equivalence identical efficiency and toxicity of two medicines containing the same active ingredient. Assessment of bioavailability of medicines for external application presents some difficulties. Their serumal concentration are usually low and can't serve as a reliable indicator of concentration of substance in skin. Meanwhile these medicines are intended for creation of therapeutic concentration in skin in case of a minimum of system side effects (Piacquadio and Kligman, 1998).

By means of test on vasoconstriction (see below) distinctions in bioequivalence between many glucocorticoids for external application protected by trademark, and their unlicensed analogs were found. Besides, even bioequivalent medicines not always have therapeutic equivalence (Olsen, 1991). It happens, first, because of distinction of bases: active ingredients can be same, and form-building — different. Secondly, these or those form-building substances as the medicines protected by trademark, and their unlicensed analogs are capable to cause allergic reactions or irritation of skin (Jackson et al., 1989). And at last, distinctions between medicines can be caused by the different speed or extent of absorption, and also storage durations.

Systemic treatment and administration of medicines in the center of lesion

For systemic treatment of skin diseases drugs usually prescribe inside, is more rare in oil (for example, Methotrexatum, glucocorticoids). Resort to systemic treatment when by means of drugs for external use it is impossible to achieve the necessary results. Treatment of onychomycoses (fungic infections of fingernails) is a bright example: drugs for external use badly get through a firm keratin of a nail plate, and treatment requires systemic prescription of medicines. The absorption of drugs at intake and at parenteral administration is discussed in hl. 1.

In the center of a lesion resort to injections of medicines mainly at inflammatory diseases, but this method is applicable also at warts, acuminate condylomas and other neoplasms of a skin. Administration of medicines in the center of a lesion has the following advantages: drug gets immediately to the pathological center, avoiding elimination at the first passing through a liver, and longly remains in the center. The absorption in a systemic blood stream differs depending on drug. For example, at an injection of 20 mg of Triamcinolonum of acetonide depression of level of a hydrocortisone in plasma within several days is possible. From the doctor practicing injections in the lesion center the awareness on an absorption of the used drugs is required.

Thus, success at treatment of skin diseases depends on a right choice not only drug, but also a way of its introduction, and also on a condition of barrier function of a skin and a dosage form.

Prospects

The comprehension of an important role of a basis for an absorption of active ingredient through a skin led to creation of modern, more effective and less dangerous medicines for external use. With the advent of liposomes and microspheres it became simpler to detain drug in the center of a lesion and to limit its action by the struck structures (for example, hair follicles).

By modification of a molecule of Retinolum the drugs which found application in many fields of medicine were framed. Retinoida for external use, having larger selectivity and smaller irritant action, significantly facilitated treatment of ordinary acnes. At a psoriasis retinoida both for intake, and for external use are used. Retinoida found the place and in medicamental prophylaxis of malignant neoplasms of a skin, and new drugs are used in treatment of a sarcoma of Kaposha and fungoides mycosis. Further changes of chemical structure of retinoid have to increase their selectivity to receptors and reduce number of side effects.

Immunomodulators appeared in the last several years. They facilitated treatment of warts, malignant neoplasms and inflammatory diseases of a skin. Deeper studying of a pathogenesis of such inflammatory diseases as a diffuse neurodermite, will allow to develop more effective treatment referred on the broken immunity link.