dermatotherapy 2.pptx

Dermatological Pharmacology - 2 dr. Hikmawan Wahyu Sulistomo, Ph.D dr. Takhta Khalasha, M.Biomed Pharmacology Department Faculty of Medicine-Brawijaya University Dermatotherapy 2 1. Antibiotics a. Acne b. Cutaneous Bacterial Infections 2. Antifungal Agents 3. Antivira...

Dermatological Pharmacology - 2 dr. Hikmawan Wahyu Sulistomo, Ph.D dr. Takhta Khalasha, M.Biomed Pharmacology Department Faculty of Medicine-Brawijaya University Dermatotherapy 2 1. Antibiotics a. Acne b. Cutaneous Bacterial Infections 2. Antifungal Agents 3. Antiviral Agents 4. Agents Used to Treat Infestations 5. Antimalarial Agents 6. Collagen Supplement 7. Topical Vitamin C 1. Antibiotics 3 1 2  The gram-positive anaerobe, 1a. Acne Propionibacterium acnes is a component of normal skin flora that proliferates in the obstructed, lipid-rich lumen of the pilosebaceous unit, where O2 tension is low. Propionibacterium acnes generates free fatty acids from sebum and interacts with toll-like receptors, which promotes microcomedo formation and inflammatory lesion Acne vulgaris is the most common dermatological disorder treated with either topical or systemic antibiotic Topical antimicrobials Topical antimicrobials commonly used in acne include benzoyl peroxide, clindamycin, erythromycin, and antibiotic–benzoyl peroxide combinations Topical monotherapy with clindamycin or erythromycin is not recommended due to a slower onset of action and potential for development of bacterial resistance; therefore, addition of benzoyl peroxide or use of combination antibiotic–benzoyl peroxide products is recommended to improve efficacy and decrease emergence of antibiotic- resistant bacteria Systemic therapy (1) Systemic therapy is prescribed for patients with acne vulgaris that is more extensive or resistant to topical therapy. There are data to support the use of tetracyclines (doxycycline, minocycline, tetracycline); macrolides (azithromycin, erythromycin); and trimethoprim-sulfamethoxazole. Antibiotics usually are administered once or twice daily, and 6–8 weeks is required for visible clinical results, with maximum effect sometimes requiring 3–6 months. Doses are tapered after control is achieved. Concomitant use with topical benzoyl peroxide may decrease development of antibiotic-resistant bacteria. Systemic therapy (2) The tetracyclines are the most commonly employed antibiotics because they are inexpensive, effective, and safe. They should not be used during pregnancy or in patients younger than 8 years Although agents in the tetracycline class are antimicrobials, efficacy in acne may be more dependent on anti- inflammatory activity. 1b. Cutaneous Bacterial Infections Gram-positive organisms, including Staphylococcus aureus and Streptococcus pyogenes, are the most common cause of SSTIs.* *SSTIs: skin and soft-tissue infections Topical Therapy (1) Topical therapy is frequently Example: used for superficial bacterial infection, wounds, and burns. Mupirocin The use of topical antibiotics Bacitracin, Neomycin, and on clean surgical wounds Polymyxin B without signs of infection is not recommended as it does not Gentamicin reduce the rate of infection and Silver Sulfadiazine there is a risk of contact dermatitis to topical antibiotics and counterproductive selection of resistant bacterial strains. Mupirocin Mupirocin inhibits protein synthesis by binding to bacterial isoleucyl-tRNA synthetase. Mupirocin is effective for treatment of S. aureus and but it is inactive against normal skin flora or anaerobes. Mupirocin is available as a 2% ointment or cream, applied two or three times daily for 5–10 days. The recommended regimen for impetigo is twice daily for 5 days Bacitracin, Neomycin, and Polymyxin B Bacitracin inhibits staphylococci, streptococci, and gram-positive bacilli. Neomycin is active against staphylococci and most gram-negative bacilli. Polymyxin B is active against aerobic gram- negative bacilli, including Pseudomonas aeruginosa. These agents are sold alone or in various combinations with other ingredients (e.g., hydrocortisone, lidocaine, or pramoxine) in a number of OTC formulations. Gentamycin Gentamicin is an aminoglycoside that inhibits protein synthesis by binding to the 30S subunit of bacterial ribosomes. It has activity for certain gram-positive bacteria, including S. aureus, and gram-negative bacteria, including P. aeruginosa. Gentamicin sulfate 0.1% cream or ointment may be applied three or four times daily to affected areas. Silver Sulfadiazine Silver sulfadiazine binds to bacterial DNA and inhibits replication. It is bactericidal against gram-positive bacteria, including MRSA, and gram-negative bacteria, including P. aeruginosa. Silver sulfadiazine is most frequently used in the treatment of partial-thickness burns or lower extremity venous stasis ulcers. Systemic Therapy Deeper or complicated SSTIs typically require systemic administration of antimicrobials, which are also useful for superficial infections with diffuse involvement or that are not responding to topical therapy. Because SSTIs are most commonly caused by streptococcal and staphylococcal species, penicillins (especially β-lactamase–resistant β-lactams) and cephalosporins are the systemic antibiotics used most frequently in their treatment. 2. Antifungal Agents Azole- chemistry  Azole- Mechanism of Action Imidazoles and triazoles thus impair the biosynthesis of ergosterol, resulting in depletion of membrane ergosterol and accumulation of the toxic product 14α-methyl-3,6-diol (14-α-methylsterols), leading to growth arrest, possibly by disrupting the close packing of acyl chains of 3. Antiviral Agents Viral infections of the skin by HPV, HSV, molluscum contagiosum virus, and VZV are common and produce a variety of lesions, including warts or blisters. Acyclovir, famciclovir, and valacyclovir are often used systemically to treat HSV and VZV infections Acyclovir, docosanol, penciclovir, and combination acyclovir/hydrocortisone topical are less effective than systemic therapies Acyclovir- history Acyclovir is a synthetic analog of the purine nucleoside, guanosine, with potent antiviral activity against herpes simplex viruses type 1 and 2, varicella-zoster virus and other viruses of the herpesvirus family. Acyclovir- Mechanisms of Action The guanine analogue acyclovir inhibits viral DNA polymerase by acting as a terminal substrate [an analog to deoxyguanosine triphosphate (dGTP)]. Incorporation of acyclovir triphosphate into DNA results in chain termination since the absence of a 3' hydroxyl group prevents the Acyclovir- pharmacokinetic The oral bioavailability of acyclovir is about 10%–30% and decreases with increasing dose. Acyclovir distributes widely in body fluids, including vesicular fluid, aqueous humor, and CSF. Acyclovir is concentrated in breast milk, amniotic fluid, and placenta. Newborn plasma levels are similar to maternal ones. Per- cutaneous absorption of acyclovir after topical administration is low. Renal excretion of unmetabolized acyclovir by glomerular filtration and tubular secretion is the principal route of elimination. t1/2 : 2.5 h (adults) ; 4 h (neonate); 20 h (anuric patients). Acyclovir- Untoward Effects Acyclovir generally is well tolerated. No excess frequency of congenital abnormalities has been recognized in infants born to women exposed to acyclovir during pregnancy Topical acyclovir in a polyethylene glycol base may cause mucosal irritation and transient burning when applied to genital lesions. Oral acyclovir has been associated infrequently with nausea, diarrhea, rash, or headache and very rarely with renal insufficiency or neurotoxicity. Acyclovir has been associated with neutropenia in neonates. 4. Agents Used to Treat Infestations Infestations with ectoparasites such as lice and scabies are common throughout the world. Permethrin Synthetic pyrethroid that interferes with insect Na+ transport proteins, causing neurotoxicity and paralysis. A 5% cream is available by prescription for the treatment of scabies, and a 1% lotion or cream rinse is available OTC for the treatment of lice. Permethrin is approved for use in infants 2 months or older. Lindane organochloride compound that induces neuronal hyperstimulation and eventual paralysis of parasites. Due to several cases of neurotoxicity in humans, the FDA has labeled lindane as a second-line drug in treating pediculosis and scabies and has highlighted the potential for neurotoxicity in children and adults weighing less than 50 kg and patients with underlying skin disorders such as atopic dermatitis and psoriasis. Lindane is contraindicated in premature infants and patients with seizure disorders. Malathion Malathion is an organophosphate that inhibits acetylcholinesterase in lice, causing paralysis and death. It is approved for treatment of head lice in children 6 years and older. The current formulation of mala- thion lotion contains 78% isopropyl alcohol and is flammable Benzyl alcohol Benzyl alcohol 5% lotion is approved for the treatment of lice in patients 6 months and older. Benzyl alcohol inhibits lice from closing their respiratory spiracles, which allows the vehicle to obstruct the spiracles and causes the lice to asphyxiate. 5. Antimalarial Agents The antimalarial agents chloroquine, hydroxychloroquine, and quinacrine are used in dermatology to treat dermatoses such as cutaneous lupus erythematosus, cutaneous dermatomyositis, polymorphous light eruption, porphyria cutanea tarda, and sarcoidosis The mechanism by which antimalarial agents exert their anti-inflammatory therapeutic effects is uncertain but may involve inhibition of endosomal toll-like receptor signaling, resulting in reduced B-cell and dendritic cell activation 6. Collagen Supplement Collagen is the major insoluble fibrous protein found in the extracellular matrix of the skin, together with elastin and hyaluronic acid. Type I collagen is the most abundant in the human body. It is also the main component of human skin (80%) with collagen type III making up the remainder of skin collagen (15%). Collagen The unique physical properties of collagen fibres confer structural integrity to the skin forming a dense network throughout the dermis. The main function of this network is to provide structural support to the epidermis. In addition, collagen and elastin together form the extracellular matrix, which gives the skin its structure, elasticity and firmness Collagen Collagen is mainly produced by fibroblast in the connective tissue. Fibroblasts are connective tissue cells in the dermis which are responsible for producing and organising the collagen matrix. The activation of fibroblasts results in an increase in the production of collagen. Collagen and Skin Aging Collagen and Skin Aging With age, the ability to replenish collagen naturally decreases by about 1.5% per year. Collagen fibres, in aged skin, become thicker and much shorter, resulting in a loss of type I collagen, which alters the ratio of collagen types. The density of collagen and elastin in the dermis declines, hence the structure and elasticity of the skin degrades, causing it to become thinner and more rigid. The ageing process results also in the loss of hyaluronic acid. This reduces the moisture, suppleness and elasticity of the skin. The diminished elasticity of the skin reduces its ability to retain its shape and it does not conform as closely to the contours of the face. The skin appears looser and sags. Lines and furrows emerge to enable movement. Gravity then pulls on the skin, all leading to sagging eyelids, bags under the eyes and jowls. Mechanism action of collagen supplement It provides the skin essential components for both elastin and collagen It is attached to the fibroblast receptors in the dermis to initiate the production of elastin and hyaluronic acid Collagen causes an increase in fibroblasts and extracellular matrix proteins that enhances the moisture content of the skin, especially the stratum corneum, as well as the elasticity of the skin, reducing wrinkling and roughness Orally consumed collagen bioactive peptides are absorbed relatively quickly because such collagen products have lower molecular weights, distributing these peptides easily across several tissues. However, topical collagen does not infiltrate the skin completely owning to its high molecular weight 7. Topical Vitamin C Normal skin contains high concentration of vitamin C, with more vitamin C is found in the epidermal layer than in the dermis, with differences of 2-5 fold between the two layers Vitamin C, as a water-soluble and charged molecule, is repelled by the physical barrier of the terminally differentiated epidermal cells It is only when pH levels are below 4 and vitamin C is present as ascorbic acid that some penetration occurs. Delivery of Topical Vitamin C Ascorbic Acid is a hydrophilic compound and has limited skin absorption. In an experiment using excised hairless mouse skin, the permeation rate of AA through the skin with the stratum corneum removed increased about 10 times compared to that of the intact skin, so the main barrier to skin absorption of AA is the stratum corneum *SVCT: sodium-ascorbate co-transporters (SVCTs) Various Strategie s to enhance the efficacy of ascorbic acid (AA) increasin g dermal collagen Role of Vitamin C in the Skin The promotion of Collagen Formation In the skin, collagen formation is carried out mostly by the fibroblast in the dermis, resulting in the generation of the basement membrane and dermal collagen matric. Vitamin C present in the fibroblast to stimulates collagen mRNA production by fibroblast and supports the synthesis of the collagen fibres. *structure of dermis Role of Vitamin C in the Skin The ability to Scavenge Free Radicals Vitamin C is a potent antioxidant and particularly effective at reducing oxidative damage to the skin when it is used in conjunction with vitamin E. Role of Vitamin C in the Skin Inhibition of Melanogenesis Vitamin C derivatives, including the magnesium phosophate ascorbyl derivative, have been shown to decrease melanin synthesis. The inhibition in melanin production by vitamin C is thought to be due to the vitamin’s ability to reduce the ortho- quinones generated by tyrosinase (key enzyme in melanin biosynthesis). Agents that decrease melanogenesis are used to treat skin hyperpigmentation in conditions such as melasma or age spots THANK YOU