Dermatologic Pharmacology Flashcards
Explain the variables of percutaneous pharmacokinetics and recognize differences between creams and ointments.
Variables:
- regional… e.g., axilla more permeable than forearm
- concentration gradient… increased conc. –> drug mass / unit time
- dosing schedule… long local t1/2 of skin reservoir may permit 1/day dosing
- vehicles/occlusion… both can maximize drug penetration
Creams: – mixture of ~half water/half oil (oil in water) with emulsifier (e.g. cetyl alcohol), water evaporates
– spread easily (i.e., good for large areas), are well absorbed, and wash off with water
– too thick to pump, so packaged in a tub or tube –
better than ointments for oozing/”wet” skin conditions
– lotions are similar albeit less viscous
Ointments: – mixture of ~20% water in ~80% oil
– oil component is made from hydrocarbons such as mineral oil or petroleum jelly
– feel greasy and are “occlusive”, meaning they stay on the surface of the skin and are not well absorbed – best used on dry skin since they trap moisture
– provide for more complete absorption of the active ingredient or medication
– ointments are less likely to cause an allergic reaction than creams, which contain preservatives
Discuss skin/hand hygiene, noting utility of components of moisturizers and sunscreens, relative microbial resistance, role of biofilms, utility of chlorhexidine, and case when soap/water is better than alcohol antiseptic.
Hand Hygiene Comments
should wash 15‐30 seconds
frequent handwashing may cause skin damage and irritation
alcohol‐based hand disinfection – is easier/faster than soap and water – rapidly effective against gram‐positive, gram‐negative and viral pathogens – not effective against C. difficile (so must use soap and water)
Moisturizer Components
emollients form an oily layer on top of the skin that traps water in the skin. common emolients: petrolatum, lanolin, mineral oil and dimethicone
humectants draw water into the outer layer of the skin common humectants: glycerin, lecithin, and propylene glycol
horny substance (keratin) softeners loosening the bonds between the top layer of cells helps dead skin cells fall off, helps the skin retain water, and gives it a smoother, softer feeling common agents: urea, alpha hydroxy acids (e.g., lactic, citric, glycolic), allantoin
Sunscreens/Sunshades
UVB radiation (280‐320 nm) causes most erythema/sunburn and skin aging and photocarcinogenesis
• UVA radiation (320‐400 nm) causes skin aging and cancer
Sunscreens: chemical compounds that absorb ultraviolet light
– p‐aminobenzoic acid (PABA) and its esters: active in UVB range
– benzophenones: wider 250‐360 nm range but less effective than PABA
– dibenzoylmethanes: active in UVA range, particularly useful for conditions such as drug‐induced photosensitivity and cutaneous lupus erythematosus
Sun protection factor (SPF): ratio of the minimal erythema dose with sunscreen to the minimal erythema dose without sunscreen, limited to 50+ by FDA
chlorhexidine
a broad‐spectrum antimicrobial agent widely used in homes and hospitals due to general efficacy on skin (including oral mucosa) and low irritability
bacterial spores- not sporicidal but prevents development of spores; inhibits spore outgrowth but not germination
mycobacteria -mycobacteriostatic (mechanism unknown) but not mycobactericidal
other nonsporulating bacteria membrane‐active agent, causing protoplast and spheroplast lysis; high concentrations cause precipitation of proteins and nucleic acids
yeasts membrane‐active agent, causing protoplast lysis and intracellular leakage, high concentrations cause intracellular coagulation
viruses- low activity against many viruses; lipid enveloped viruses more sensitive than nonenveloped; effect possibly on viral envelope (e.g., lipid moieties)
protozoa- has activity against trophozoites, less toward cysts
biofilm antibiotic resistnce mechanism pertains to limited penetration and antibiotic neutalization
Discuss the basics of skin wound management, and the agent that promotes skin growth.
antiseptic wash solutions
– have minimal action against bacteria
– potentially impede wound healing through toxic effects on normal tissue
• antibiotic therapy should be reserved for wounds that appear clinically infected
Wound Debridement
- removing dead tissue and debris promotes wound healing by limiting protease production and conserving the local resources needed for healing
- low‐pressure irrigation with normal saline: should be routine since it flushes bacteria and removes loose material
- surgical debridement: appropriate for removing large areas of necrotic/infected tissue
- enzymatic debridement: variety of products, mixed results; collagenase may promote endothelial cell and keratinocyte migration for angiogenesis and epithelialization
- biologic debridement: maggot therapy has negative perceptions, but does result in liquefaction of necrotic tissue while leaving healthy tissue intact… however, pressure ulcer healing time is not consistently reduced
becaplermin:
platelet derived growth factor that promotes cell proliferation and angiogenesis – only agent approved for treatment of chronic diabetic foot ulcers – has a black box warning for malignancy… use of >3 tubes increases risk of malignant complications ~ 4X
epidermal growth factor: does not significantly improve epithelialization
Wound Dressings
general principles: wounds should be kept moist, and should not be exposed to air as done historically
– occluded wounds heal 40% faster and have less scarring
– wounds are exposed to their own fluid, a mix of metalloproteases and cytokines
consensus opinion on choices:
– hydrogelsfor debridement stage
– foam and low‐adherence dressings for the granulation stage
– hydrocolloid and low‐adherence dressings for epithelialization stage
Topical Antibacterial Agents
bacitracin
peptide antibiotic, inhibits bacterial cell wall synthesis
- active against gram‐ positive organisms, also active against most anaerobic cocci, neisseriae, tetanus bacilli, diphtheria bacilli
- often causes allergic contact dermatitis, and rarely immunologic allergic contact urticaria
- poorly absorbed through the skin, so systemic toxicity is rare
neomycin
- aminoglycoside antibiotic, binds to 30S ribosomal subunit to inhibit protein synthesis
- active against gram‐ negative organisms
- often causes allergic contact dermatitis, and cross‐sensitization to other aminoglycosides can occur
- poorly absorbed through the skin, so systemic detection is rare
polymixin B
- peptide antibiotic, binds to phosphor‐lipids to alter permeability and damage bacterial cytoplasmic membrane
- effective against gram‐ negative organisms, including P. aeruginosa, E. coli, Enterobacter, and Klebsiella
- rarely causes allergic reaction
Describe the mechanism of action and indications for common antibacterial, antifungal and antiviral medications applied topically to treat skin infections.
Topical Antifungal Agents ‐1
topical imidazoles, block ergosterol synthesis, have a wide range of activity against dermatophytes and yeasts
– miconazole … topical application as a cream or lotion; vaginal cream or suppositories for use in vulvovaginal candidiasis
– clotrimazole … topical application to the skin as a cream or lotion; vaginal cream and tablets for use in vulvovaginal candidiasis
– efinaconazole … onychomycosis treatment, given for 48 weeks, complete cure in ~15% ‐18%
– ketoconazole … cream for topical treatment of dermatophytosis and candidiasis, shampoo or foam for seborrheic dermatitis
Topical Antifungal Agents ‐ 2
ciclopirox
– prescription synthetic broad‐spectrum topical antimycotic agent, disrupts macromolecular synthesis
– activity against dermatophytes, Candida and Malassezia
– low incidence of adverse reactions and contact dermatitis
terbinafine
– allylamine, selectively inhibits squalene epoxidase, a key enzyme for the synthesis of ergosterol
– highly active against dermatophytes but less active against yeasts
– cream can cause local irritation, avoid contact with mucous membranes
tolnaftate
– synthetic antifungal compound, mechanism uncertain but distorts hyphae/stunts mycelial growth
– effective topically against various dermatophyte and malessezia infections but not Candida
– generally well tolerated and rarely causes irritation or allergic contact dermatitis
Topical Antifungal Agents ‐ 3
nystatin
– binds to fungal sterols, alters membrane permeability
– limited to topical treatment of cutaneous and mucosal candida infections (hold in mouth before swallowing) because of its narrow spectrum and negligible absorption from the gastrointestinal tract following oral administration
– non‐irritating topically; mild nausea and diarrhea if swallowed
amphotericin B
– binds to fungal sterols, alters membrane permeability
– limited to topical treatment of cutaneous candida infections
– well tolerated, but may cause a temporary yellow staining of the skin
Oral Antifungal Agents for Cutaneous Infections
fluconazole, itraconazole
– broad spectrum; can treat tinea versicolor
• terbinafine – given orally to treat onychomycosis
• griseofulvin
– given orally to treat dermatophyte infections of scalp and non‐ hairy skin caused by Epidermophyton, Microsporum, and Trichophyton
– mechanism of action unclear – ineffective against Candida and Malassezia
Topical Antiviral Agents
acyclovir
– synthetic guanine analog with inhibitory activity against herpes simplex types 1 and 2
– used for the treatment of recurrent orolabial herpes simplex virus infection (herpes labialis) in immunocompetent adults
– ointment, cream and buccal tablet formulations available
Review common causes of pruritus and list the names and mechanisms of action for various types of therapeutic agents; also recognize that topical glucocorticoids are arranged/used according to their different potencies.
Systemic Causes of Pruritus
Kidney disease • Chronic renal failure
Liver disease • Intrahepatic and extrahepatic biliary obstruction (cholestatic pruritus)
Endocrine/metabolic • Diabetes • Hyperthyroidism • Hypoparathyroidism • Myxedema • Hypercalcemia
Blood • Iron deficiency anemia • Polycythemia • Lymphatic leukemia • Hodgkin lymphoma
Nervous system • Generalized neuropathic pruritus (e.g. following stroke or small fiber neuropathy) • Neurotic excoriations, skin picking
Reproductive • ~ 2% of pregnancies, especially 3rd trimester; perhaps due to cholestasis • Generalized itch is a common symptom after menopause
Topical Therapies for Pruritus
Barrier repair: creams, moisturizers, emollients-Low pH products may be particularly useful
Topical corticosteroids-Not directly antipruritic, may be useful in pruritus due to inflammatory skin dermatoses
Topical calcineurin inhibitors-Particularly useful in anogenital pruritus, may experience transient burning and stinging
Doxepin (H1 antagonist?)-Avoid in children, 20 to 25 percent risk of sedation
Menthol (TRPM8 agonist)-Useful in patients who report cooling as an alleviating factor
Capsaicin (TRPV1 agonist)-Particularly useful in neuropathic itch, may experience initial transient burning
Salicylic acid (COX inhibitor and keratolytic)-Useful in lichen simplex chronicus, avoid in acute inflammatory dermatoses and children
Local anesthetics-(Pramoxine) found in a variety of OTC remedies along with hydrocortisone; e.g., useful for pruritus on face and that associated with CKD,
Lidocaine Useful in neuropathic pruritus
Rosacea
brimonidine… α 2‐adrenergic agonist applied as a topical gel, vasoconstricts by stimulating post‐ synaptic vascular α2 receptors.
oxymetazoline… mixed α1A/α 2‐adrenergic agonist vasoconstrictor applied as a topical cream, approved 2017
Eyes
naphazoline, tetrahydrozoline, phenylephrine and oxymetazoline… eye drops are all adrenergic receptor agonists
List agents used to treat ectoparasitic infections and describe their mechanisms of action.
Killing Ectoparasites
malathion… topical agent, organophosphate cholinesterase inhibitor
permethrin… topical agent, binds to insect Na + channels, blocks membrane repolarization
ivermectin… administered orally, binds to glutamate‐gated Cl‐ channels in invertebrates, hyperpolarizes the nerve and muscle cells
lindane… topical agent, toxicity causes to be used only after other agents fail, disrupts GABAergic transmission in insects
Discuss management of acne, and describe the mechanisms of action and adverse effects of common therapeutic agents.
Topical Retinoids
Tretinoin-Once daily, at bedtime, Select adverse effects-Local skin irritation, dryness, and flaking; sun sensitivity NOTE: Atralin® contains soluble fish proteins, use with caution in patients with known sensitivity or allergy to fish
Adapalene-Once daily, at bedtime, Select adverse effects: Local skin irritation, dryness, and flaking; sun sensitivity
Tazarotene-Once daily, at bedtime, Select adverse effects: Pregnancy category X; local skin irritation, dryness, and flaking; sun sensitivity
Topical Antimicrobials
Benzoyl peroxide-Twice daily, Local skin irritation; may bleach hair or clothing
Clindamycin-Twice daily Once daily (foam), Rare risk of pseudomembranous colitis
Erythromycin
Azelaic acid-Local skin irritation
a dicarboxylic acid , a white powder found in wheat, rye and barley where it is involved in the plant defense response to an infection
- it kills acne bacteria and decreases the production of keratin
- it is used to treat mild to moderate acne, and also treats post‐inflammatory hyperpigmentation
Oral Antibiotics
Tetracycline-500 mg twice daily-Photosensitivity, gastrointestinal distress; contraindicated in pregnancy and young children
Doxycycline-Photosensitivity, gastrointestinal distress; contraindicated in pregnancy and young children
Minocycline-Dizziness, drug‐induced lupus, skin discoloration; contraindicated in pregnancy and young children
Erythromycin-Gastrointestinal distress
Azithromycin-Gastrointestinal distress
Trimethoprim‐ sulfamethoxazole-Stevens‐Johnson syndrome, toxic epidermal necrolysis
Hormonal Agents
Combination oral contraceptives (estrogen/progestin)-Nausea, breast tenderness, weight gain, thromboembolic events
Spironolactone-Contraindicated in pregnancy; menstrual irregularity, breast tenderness, minor gastrointestinal symptoms, orthostatic hypotension, hyperkalemia, dizziness, headaches, fatigue
Oral Retinoid
Oral isotretinoin-Teratogenicity (absolutely contraindicated in pregnancy), mucocutaneous effects, hypertriglyceridemia, others
Discuss management of psoriasis, and describe the mechanisms of action and adverse effects of common therapeutic agents.
Topical Therapies
Emollients • Corticosteroids (initial choice for mild to moderate psoriasis)
Topical vitamin D analogs: – calcipotriene – calcitriol (mechanism unclear, but reduce keratinocyte proliferation)
Anthralin (mechanism unknown but has anti‐inflammatory effects and slows )
Systemic Therapies
• methotrexate •
apremilast… (new PDE4 inhibitor; definitely works with short‐term diarrhea as common side effects; not as broadly effective as some other choices; ~ as expensive as biologics)
- retinoids
- systemic calcineurin inhibitors (e.g., cyclosporine) •
biologic agents (more in RA notes on first 3)
– etanercept… (TNFα inhibitor)
– infliximab… (TNFα inhibitor)
– adalimumab… (TNFα mAb)
– ustekinumab… (IL‐12 and IL‐23 mAB)
– secukinumab, ixekuzumab… (IL‐17A mAb)
apremilast
inhibits phosphodiesterase 4 (PDE4),cAMP levels
used for: moderate to severe plaque psoriasis • active psoriatic arthritis
oral
crisaborole: PDE4 inhibitor recently approved as topical therapy for dermatitis
ustekinumab
targets proinflammatory cytokines IL‐12 and IL‐23
used for: plaque psoriasis psoriatic arthritis Crohn disease
Toxicities: generally well tolerated, but increases risk for infections
secukinumab-targets proinflammatory cytokine interleukin 17A
: blunts IL‐17A effects, thereby decreasing its ability to induce the production of many other proinflammatory signaling
used for: ankylosing spondylitis plaque psoriasis psoriatic arthritis
increases risk for infections
Discuss management of actinic keratosis, and describe the mechanisms of action and adverse effects of common therapeutic agents.
Liquid nitrogen cryotherapy
- Surgical therapy
- Pharmacotherapy
– Topical 5‐fluorouracil (see next)
– Imiquimod… a topical immune response modifier that stimulates local cytokine induction, is an effective therapy
– Ingenol mebutate…a substance derived from the sap of the Euphorbia peplus plant, is an effective treatment; has two stages:
1) initial disruption of cell plasma membranes and mitochondria leading to cell necrosis (chemoablation) ans
2) neutrophil‐mediated antibody dependent cellular cytotoxicity that eliminates remaining tumor cells
– Topical diclofenac… an NSAID, benefits suggest PG’s may be important for skin carcinogeneis
– Retinoids… (discussed above)
Photodynamic (Red Light) therapy: LED emits strong 635 nm light
- Dermabrasion: surgical skin planing
- Chemical peels: e.g., with trichloroacetic acid
Topical 5‐Fluorouracil
inhibits thymidylate synthetase, a critical enzyme in the synthesis of DNA
- the lack of DNA synthesis in fast‐growing dysplastic cells prevents cell proliferation and causes cell death
- causes inflammation and destruction of the lesions (see next slide)
- after 4‐6 weeks skin will have progressed from erythema through blistering, necrosis with erosion, and then re‐epithelialization
Recognize treatment strategies and agents used to treat skin cancer.
• surgical removal/ablation:
– curettage and electrodessication
– Mohs micrographic surgery
– X‐ray radiation – cryosurgery
– photodynamic therapy
– laser surgery
• topical medications: – imiquimod – 5‐fluorouracil • advanced BCC – vismodegib or sonidegib: both oral “hedgehog” signaling pathway inhibitors
treatment for melanoma
conventional chemotherapy…
– dacarbazine is FDA‐approved – ± (carmustine and tamoxifen) or (cisplatin and vinblastine) • MAP kinase pathway inhibitors
– if BRAF V600D gene mutation (seen in ~60%)…
– vemurafenib then inhibits, results in apoptosis
List common causes of alopecia, the drugs used to treat it and their mechanisms of action.
treatment
– minoxidil (first‐line):
- vasodilates due to K +‐channel opening
- promotes hair growth by increasing the duration of anagen (growth phase), shortening telogen (rest phase), and enlarging miniaturized follicles
– anti‐androgens (second‐line when minoxidil fails)
- spironolactone (androgen partial agonist)
- finasteride (blocks dihydrotestosterone synthesis)
- flutamide (androgen antagonist)
Management of Alopecia Areata
chronic, relapsing immune‐mediated inflammatory disorder affecting hair follicles resulting in non‐ scarring hair loss
treatment
– intralesional or topical corticosteroids
– topical immunotherapy … contact allergen such as diphenylcyclopropenone (DPCP) is used to cause contact dermatitis, which causes hair growth for unknown reason
