Dermatological Pharmacology - 1 PDF

Dermatological Pharmacology - 1 dr. Hikmawan Wahyu Sulistomo, Ph.D Pharmacology Department Faculty of Medicine-Brawijaya University Topic 1 Principles of Dermatological Pharmacology 2 Glucocorticoids 3 Antihistamines  1 PRINCIPLES OF DERMATOLOGICAL PHARMACOLOGY...

Dermatological Pharmacology - 1 dr. Hikmawan Wahyu Sulistomo, Ph.D Pharmacology Department Faculty of Medicine-Brawijaya University Topic 1 Principles of Dermatological Pharmacology 2 Glucocorticoids 3 Antihistamines  1 PRINCIPLES OF DERMATOLOGICAL PHARMACOLOGY Structure of Skin 1. Epidermis Stratum Corneum Barrier to drug absorption and water loss Living Epidermis Metabolically-active cells 2. Dermis and Its Blood Vessels Mechanical strength and flexibility 3. Hypodermis Insulation, cushioning, and an energy reservoir. 2 3 Active Drug e.g. VEHICLE Principle of 1 Fig. 2. Classification of pastes : (a) the retinoids, cortico- Ingredients Structural Matrix Human 2-phase pastes consist of 2 immiscible com- Adherence ponents, one (the dispersed or inner phase; Skin steroids Structural Matrix Agents: e.g. hydrocarbons, alcohols, MonophasicSystems: factor powder) being suspended in the other (the continuous or outer phase), (b) the 3-phase e.g. ointm ents celluloses, silicones pastes consist of a 2-phase emulsion (oil in Biphasic Systems: water or water in oil) with high concen- Auxiliary Agents: e.g. cream s trations of incorporated powder (cream e.g. benzoic acid, phenols, pastes). benzalkon ium chloride, Tri-(multi-)phasic Systems: butylated hydroxytoluene Fig. 3. The pharmacopoeial nomenclature Topical e.g. cream pastes used to classify topical formulations. Fig. 4. Principle of topical preparations : example of a topical preparation comprised of individual ingredients that form a struc- 4 tural matrix. 3 Therapy preparations, but also holds true for most pharmaceutical ly under debate [26, 50–53]. In clinical practice, the ques- 2 preparations. The visibility of the application site (target organ), the tactile sensations when the topical preparation is applied to the skin and the appearance, ease of use and consistency of preparations probably led to the distinctive Potency Efficacy tion is often asked whether creams, gels, ointments or liposomes are better in delivering a drug to the skin in terms of promoting the drug absorption and therapeutic of Active effect. Certainly, cosmetic aspects of the delivery sys- Vehicle importance of the formulation type and the ingredients of tem, a result of the structural matrix, may have an factor the vehicle. These circumstances have led to extensive molecule influence on compliance and are therefore of clinical rele- discussions on the ‘vehicle effect’ where the various inter- vance. H owever, drug delivery to the skin is controlled by est groups have different conceptions and different expec- the vehicle excipients as these affect partitioning into and Adherence Poor adherence to topical treatment is a common cause of poor response to drugs and is linked with poor outcomes in diseases such as psoriasis, atopic dermatitis, and acne Poor adherence: Intentional: driven by the patient’s perception of the need for treatment weighed against their concern for toxicities and other costs Unintentional: forgetfulness or lack of knowledge on prescribed regimens Poor adherence: Primary nonadherence refers to when patients do not fill their prescription or initiate treatment. Secondary nonadherence occurs when patients initiate treatment but use the medication poorly. 1. Human Factor Pharmacokinetics in the skin Compartments affect topical pharmacokinetics Skin surface Stratum corneum Viable tissue. 1. Human Factor  Mechanisms of Percutaneous Absorption ∼0.5 to 2.0 mg/cm2 Preferable characteristics of topical drugs: Low molecular mass (≤500 Da); Adequate solubility in both oil and water; and a high partition coefficient so the drug will selectively partition from the vehicle to the stratum corneum For example, diffusion coefficient for water in an aqueous solution is: 2.5 × 10−5 cm2/s, suggesting that a water molecule would migrate over a 10-μm path in 0.4 ms 1. Human Factor SKIN SURFACE FORMULATIONS Formulation purposes to remain on the skin surface (sunscreen products and cosmetics) to be delivered to compartments in the skin (topical formulations) to migrate across the skin into the central compartment (transdermal formulations) When a topical product is mixed with another product—for example, mixing 0.1% triamcinolone cream with a moisturizing cream or other product—the activity of the resulting product is not predictable. Although a 1:1 mixture would reduce the concentration of triamcinolone from 0.1% to 0.05%, the physical chemical properties of the vehicle will have changed. 1. Human Factor SKIN SURFACE  PENETRATION PATHWAYS IN STRATUM CORNEUM Intercellular penetration Follicular penetration Intracellular penetration. 1. Human Factor STR. CORNEUM  Absorption of most drugs across the skin is a passive process A hydrated stratum corneum allows more percutaneous absorption and often is achieved through the selection of drugs formulated in occlusive vehicles. Heat generally increases penetration 1. Human Factor STR. CORNEUM (Maibach, et al 2015)  Children have a greater ratio of surface area to mass than adults do, so the same amount of topical drug can result in greater systemic exposure. Preterm infants have a markedly impaired barrier function until the epidermis keratinizes completely 1. Human Factor STR. CORNEUM 1. Human Factor STR. CORNEUM  SKIN METABOLISM Skin contains a wide range of enzymatic activities, including phase I oxidative, reductive, hydrolytic, and phase II conjugation reactions, Alterations in skin metabolism have been implicated in a range of diseases, including hirsutism and acne, and they may be Arylamine-type hair dye ingredients are also subject to relevant to the risk of topical metabolism in human and animal skin, resulting in N- exposure to carcinogens. acetylated metabolites. The enzyme responsible is believed to be epidermal N-acetyltransferase-1. 1. Human Factor VIABLE TISSUE  RESORPTION the uptake of compounds by the cutaneous microvasculature, is directly related to the surface area of the exchanging capillaries as well as their blood flow For most compounds and situations, resorption does not change the rate of diffusion to the central compartment after topical applications 1. Human Factor VIABLE TISSUE The vehicle The vehicle is the inactive part of a topical preparation that brings a drug into contact with the skin Vehicle of a topical formulation often has beneficial nonspecific effects by possessing cooling, protective, emollient, occlusive, or astringent properties The ideal vehicle criteria Nonirritating, Non- allergenic, Cosmetically acceptable Easy to use Pharmacologically inert and should readily release the drug for enhanced, controlled or targeted absorption 2. The vehicle 2. The vehicle  POWDER OINTM ENT-BASED PREPARATIONS WATER-BASED PREPARATIONS Protective paste Drying pastes Gels, shake lotions Liniments suspensions LIQUID GREASE (lotions, w et soaks, (ointm ent, oils) com presses) W/O CREAMS O/W CREAMS (oily cream s) (aqueous cream s) M ore suitable for ‘dry’ or M ore suitable for ‘w et’ exudative chronic derm atoses or acute derm atoses Emulsions 2. The vehicle The Choice of Vehicle 1. Acuity and Type of the Disease The principle of ‘wet-on-wet’/ ‘dry-on-dry’. a ‘wet’ dermatosis may subsequently be treated with either a drying paste or an oil/water cream, a ‘dry’ dermatosis may be treated with either a hydrous ointment, water/oil cream or even an occlusive ointment 2. Skin Type, Skin Status Vehicles with hydrophilic properties are suitable for oily and normal skin conditions whereas vehicles with lipophilic properties are more suitable for dry skin conditions 3. Localization of the Disease 4. Environmental Factors 5. Cosmetic Consideration 2. The vehicle 2. The vehicle Tab le 8. L ocalization, skin status and vehicle used in different loca- vehicles (e.g. tions should be des tions of usage Localization Status Forms be kept in min H airy skin dry solutions, w/o cream oily solution, gel C osm e tic C Face dry w/o cream Cosmetic oily solution, o/w cream ance, odor, a Ears oily o/w cream Body/extremities dry ointment, w/o cream after applicat oily o/w cream vehicle and d I ntertriginous area humid drying pastes, o/w cream influence con H ands/feet dry during the day: o/w or w/o cream Financially th oily during the night: ointment, w/o cream fer of consum N ails dry solution, lacquer product. The 2. charac The vehicle  2 GLUCOCORTICOIDS Mechanisms of glucocorticoid action The double-pronged inhibitory effect of corticosteroids on NF-kB. GRE,Glucocorticoid- responsive element; IkBa, NF-kB inhibitory factor; NF-kB, nuclear factor-kappa B (Norris D.A, 2005) Topical Glucocorticoids  Therapeutic Uses The steroid is selected on the basis of its potency, the site of involvement, and the severity of the skin disease. Often, a more potent steroid is used initially, followed by a less potent agent. Twice- daily application of topical glucocorticoids suffices; more frequent application does not improve response. (Goldminz A.M, et al, 2021)  Toxicity Chronic use of class 1 topical glucocorticoids can cause skin atrophy, striae, telangiectasias, purpura, and acneiform eruptions. Because perioral dermatitis and rosacea can develop after the use of fluorinated compounds on the face, they should not be used on this site. Occlusion increases the risk of HPA axis suppression. skin atrophy striae telangiectasias purpura acneiform eruptions doi: 10.4103/0019-5154.139872: 10.4103/0019-5154.139872 Systemic Glucocorticoids Systemic glucocorticoid therapy is used for severe dermatological illnesses and generally is reserved for allergic contact dermatitis to plants (e.g., poison ivy) and for life-threatening vesiculobullous dermatoses such as pemphigus vulgaris and bullous pemphigoid. Toxicity (Telo, GH. 2020)  3 Antihistamines Role in Allergic Responses (Huang H, 2018)  Chemical itch mediators acting as pruritogens on C fibers Histamine Receptor H1 and H2 receptors are distributed widely in the periphery and in the CNS and their activation by histamine can exert local or widespread effects (Ennis M, Tiligada E. 2018) H1 antagonists/ Anti histamine (AH-1) Second-generation H1 receptor antagonists lack anticholinergic side effects and are described as nonsedating largely because they do not cross the blood-brain barrier Mechanism of action Effects on Physiological Systems ADME The H1 antagonists are well absorbed from the GI tract. Peak plasma concentrations are achieved in 1–3 h, and effects usually last 4–6 h for first-generation agents and longer for 2nd generation H1 antagonists. Peak concentrations of these drugs in the skin may persist long after plasma levels have declined (see note). All first-generation and most second-generation H1 antagonists are metabolized by CYPs The H1 antagonists that are metabolized are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. Therapeutic Uses Allergic Diseases Certain allergic dermatoses respond favourably to H1 antagonists. The benefit is most striking in acute urticaria. Common Cold H1 antagonists are without value in combating the common cold. Motion Sickness, Vertigo, and Sedation H1 antagonists are useful for milder cases and have fewer adverse effects. These drugs include dimenhydrinate and the piperazines (e.g., cyclizine, meclizine). Adverse Effects The most frequent side effect of first-generation H1 antagonists is sedation. H1 antagonists such as cyproheptadine may increase appetite and cause weight gain. The antimuscarinic actions Adverse Effects (cont.) Because H1 antihistamines cross the placenta, caution is advised for women who are or may become pregnant Antihistamines can be excreted in small amounts in breast milk, and first- generation antihistamines taken by lactating mothers may cause symptoms such as irritability, drowsiness, or respiratory depression in the nursing infant Second-generation antihistamines are preferred for elderly patients (>65 years of age), especially those with impaired cognitive function, because of the sedative and anticholinergic effects of first-generation drugs First-generation antihistamines are not recommended for use in children because their sedative effects can impair learning and school performance. THANK YOU