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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5192_Библиотеки_им_академика_М_И_Перельмана.pdf
2.7 Phototherapy
Used primarily in invasive Candida inections and invasive
aspergillosis (second line)
Unique AEs: acial swelling (caspoungin), ↑ alkaline
phosphatase (caspoungin), hypokalemia (caspoungin),
and hematuria/proteinuria (caspoungin)
precipitated sulur is sae in pregnant women and
children under 2 months o age with scabies;
permethrin is sae in pregnant women and children
over 2 months o age; topical thiabendazole
compound may be helpul or cutaneous larva
migrans
VIII. Tavaborole
Novel oxaborole; inhibits protein synthesis enzyme
cytosolic leucyl-transer RNA synthetase
Topical solution or onychomycosis; complete cure rate
5 6.5%
Antiparasitic agents (Tables 2.7 and 2.8)
Interesting acts about drugs not in the tables:
benzyl benzoate may → disulfram-like reaction;
Table 2.7 Systemic Antiparasitic Treatments
Agent Mechanism Uses Adverse Eects (AEs)
Ivermectin Binds glutamate-gated chloride
Albendazole
Thiobendazole Inhibits umarate reductase FDA: strongyloides, cutaneous larva migrans,
CNS, Central nervous system; FDA, Food and Drug Administration; GI, gastrointestinal; HTLV-1, human T-lymphotropic virus type 1; SJS, Stevens-Johnsons
syndrome; SNPs, single nucleotide polymorphisms.
ion channels o parasite nerve/
muscle cells → ↑ membrane permeability → hyper-polarization →
death
O note, resistance can occur due to
SNPs o P-glycoprotein-like protein
Stops tubulin polymerization →
immobilization and death o parasite
FDA: onchocerciasis, intestinal strongyloidiasis
(secondary to Strongyloides stercoralis),
rosacea (topical)
O-label: scabies (0.2 mg/kg/dose po q1wk 3
2doses), cutaneous larva migrans, and
pediculosis
FDA: neurocysticercosis and hydatid disease
O-label: Ascaris lumbricoides, Trichuris trichiura,
Enterobius vermicularis, Ancylostoma duodenale and Necator americanus (hookworms),
Taenia, Strongyloides stercoralis, Giardia,
scabies
and visceral larva migrans
O-label: trichinosis, uncinariasis, Necator,
Ancylostoma, trichuriasis, and ascariasis
2.7 PHOTOTHERAPY
Divided into ultraviolet A (UVA) (320–400 nm) and
ultraviolet B (UVB) (280–320 nm) modalities
Doses o light determined by skin type usually or
70% o minimum erythema dose (MED; lowest
dose that results in minimally visual erythema)
and increased as tolerated each visit up to a maximum
dose
Commonly rashes, pruritus, ever, and lymph-
adenopathy (less with scabies inection)
Rarely death and encephalopathy when used
in patients with loiasis
Mazzotti reactions 5 rash/systemic symp-
toms/ocular reactions; occurs in patients
with onchocerciasis → doxycycline helps
reduce these reactions
Bone marrow suppression (↑ risk i patient
has liver disease), aplastic anemia, agranulocytosis, hepatotoxicity, GI AEs, rash
May ↑ theophylline levels
Resistance higher in patients with HTLV-1
inection
Hepatotoxicity, GI AEs, CNS AEs, SJS
May ↑ theophylline levels
Table 2.8 Topical Antiparasitic Treatments
Agent Mechanism Uses Adverse Eects (AEs)
Permethrin Related to pyrethrins, which come rom fowers
Malathion Organophosphate that inhibits
Spinosad
Lindane
Abametapir Metalloproteinase inhibitor P. capitis in patients aged 6 months or older Local irritation
Crotamiton Mechanism unknown but is toxic to scabies
o genus Compositae
Disables sodium transport channels on the cell
membranes o arthropods → paralysis
acetylcholinesterase in arthropods →
neuromuscular paralysis
Instigates arthropod motor neurons → paralysis
Organochlorine → ↓ neurotransmission →
arthropod respiratory/muscular paralysis
mites and has anti-pruritic eects
Scabies (5% cream is the treatment o
choice; neck down application—2 overnight
applications separated by 1 week) and
Pediculosis capitis (1% cream rinse)
P. capitis (0.5% lotion; most eective treatment
in the United States; treatment o choice in
children $ 6 years old)
P. capitis (very rapid eect: 10-minute
application)
Scabies and P. capitis Seizures i ingested or multiple
Scabies (10% cream or lotion; neck down
application once and then again in 24 hours with
no shower till 48 hours ater the initial application)
Local irritation, rare neurotoxicity
(numbness, tingling, tremors, and
at high exposures, paralysis and
seizures)
Local irritation
Potentially fammable
Malodorous
I ingested → symptoms o organophos-
phate poisoning/↓ cholinesterase
Local irritation
applications
Aplastic anemia, leukemia
Local reaction; requent treatment
ailure
65
CHAPTER 2 Dermatopharmacology
UVA modalities
Psoralen plus UVA (PUVA)
Photochemical reaction between psoralen
(8-methoxypsoralen usually) and UVA
■
Psoralen (0.4–0.6 mg/kg 1–2 hours beore UVA) can be
administered orally or topically
O note, beore UV exposure, psoralen intercalates
into DNA
Photoactivated psoralen molecules orm 3,4 or 4’,5’
cyclobutane monounctional adducts to pyrimidines
in DNA → inter-strand DNA cross-link → ↓ DNA
synthesis/cell cycle arrest
PUVA → selective immunosuppression, selective
cytotoxicity (via production o ROS and ree
radicals), and melanocyte stimulation
Psoralens ideally taken under asting conditions,
because ood slows absorption
Absorption and bioavailability vary widely with
8-methoxypsoralen
Metabolized by liver
Used in many inammatory dermatoses including
atopic dermatitis, psoriasis, vitiligo, CTCL,
photodermatoses (using desensitization protocols),
GVHD, and lichen planus
AEs include: nausea/vomiting (ood may help),
phototoxic reactions (e.g., symptomatic erythema
and pruritus), hepatic toxicity, bronchoconstriction,
HSV recurrences, cardiovascular stress, CNS
disturbances, photoaging, melanoma, and NMSC
(SCC .. BCC; usually i $ 250 treatments), and
ocular issues (e.g., cataracts)
UV-opaque goggles and ace/genital protection in
unit; UV-opaque glasses ater exposure until sunset,
along with photoprotection
Contraindications: lactation and photosensitizing skin
disorders (LE, albinism, porphyria, XP); autoimmune
blistering disease has been induced by PUVA)
■
Treatments administered two to three times per week
initially till mostly clear, then a maintenance schedule
where radiation dose is kept the same and visit
requency slowly decreased (even to one treatment a
month), then stopped
■
Sae in combination with other treatments (e.g.,
topicals, MTX, acitretin, and UVB)
UVA-1 (340–400 nm)
Treatments can be low, medium, or high dose
Dose based on MED as sensitivity to UVA-1 can vary
greatly between people
Not many centers in the United States have UVA-1 units
and not necessarily superior to PUVA and/or NB-UVB
Various skin disorders including SLE (low dose),
scleroderma/other sclerodermoid skin conditions (need at
least 30 treatments), atopic dermatitis, and MF
AEs include erythema in the short-term; no long-term
studies or AEs
UVB modalities
MoA: ↓ DNA synthesis (i.e., in psoriatic epidermis)
and ↑ p53 → cell cycle arrest/keratinocyte apoptosis;
↓ proinammatory cytokines, ↓ Langerhans cells in
skin
Narrowband UVB (311–313 nm)
■
Treatments given three times a week initially (based on
skin type or 70% MED) and increased by 10%–15%
each treatment; may have to adjust the dose based on
erythema severity
■
UV-opaque goggles during treatment and covering ace/
genitals
■
AEs: skin reactions (e.g., erythema or pruritus),
mucosal reactions (recurrent herpes labialis, or
blepharitis), exacerbation o SLE and blistering
disorders. No signifcant risk o skin malignancy
■
Used in psoriasis (most commonly prescribed
phototherapy), vitiligo, MF (patch and plaque), atopic
dermatitis, photodermatoses (using desensitization
protocols), and pruritus (idiopathic and secondary)
■
Similar contraindications to PUVA
Broadband UVB—280–320 nm; more convenient in
darker-skinned individuals than NB-UVB (shorter
treatment times), but largely has been replaced by
NB-UVB
Excimer laser—308 nm; high-intensity treatment with
higher efcacy than standard NB-UVB or treating smaller
surace areas (,2 cm2; e.g., in psoriasis and vitiligo)
Extracorporeal photochemotherapy
Pheresis via venous catheter in arm vein → blood cells
separated into leukocyte-rich buy coat and RBCs
(returned back to patient) → 8-methoxypsoralen added to
leukocytes → UVA radiation → reinusion (net gain o
500 mL o uid, but initially 200 to 400 mL are pheresed)
■
Usually 2-day cycle every 4 weeks and slow weaning
ater desired response
Various eects on immune system, including T cells (e.g.,
apoptosis o activated T cells, induction o regulatory T
cells/immunologic tolerance), cytokines (e.g., avors
immunoregulatory cytokines), and dendritic cells (↓#)
Eective in CTCL (selectively targets lymphoma cells; can
be used in combination with other treatments) and other
dermatoses (e.g., scleroderma, chronic GVHD,
nephrogenic systemic fbrosis, and pemphigus)
Contraindicated in severe cardiac disease (because o
difculty in handling added uid volume); caution in
patients with low BP, hematocrit, and CHF
AEs: nausea, photosensitivity, hypotension, CHF, and
tachycardia
Photodynamic therapy (PDT)
Activation o topical photosensitizer by light
■
Aminolevulinic acid (ALA): activated by blue light
(Blu-U device); no need or occlusion
■
Methyl aminolevulinate (MAL): activated by red light
(Aktilite) and is more lipophilic; occlusion
recommended
■
These photosensitizers are ultimately converted to
protoporphyrin IX within cells → activated to a higher
energy state (along with production o ROS, including
singlet O2) primarily with light ≈ 410-417 nm (Soret
band, blue), but also has other peaks (e.g., 635 nm,
66
2.8 Miscellaneous Agents
red) → localize by mitochondria → necrosis/apoptosis
o malignant cells
Neoplastic cells accumulate more porphyrins than
normal cells—thus PDT eective in actinic
keratoses and NMSCs
O note, protoporphyrin IX is also elevated in the
inherited condition, protoporphyria
In acne, targets sebaceous glands and C. acnes,
which accumulates porphyrins (light alone is
eective in acne 1/– photosensitizer)
■
Only FDA-approved indication is actinic keratosis
(≈90% response on individual lesions), but also
used in BCC, SCCIS, acne, photoaging, hidradenitis,
and MF
■
Technique: (1) skin cleansed (acetone or ALA and
gentle curette debridement o scale/crust or MAL);
(2) photosensitizer applied; (3) incubation time (3–
exposure (37 J/cm2 or MAL: 7–9 minutes, 10 J/cm2 or
ALA: 16 minutes); and (5) retreat in 7 days or MAL
and 1 to 2 months or ALA i needed
■
Protective eyewear during procedure and avoid sunlight
or 48 hours
■
AEs: phototoxic reactions/photosensitivity, hypo-/
hyperpigmentation, hypersensitivity to photosensitizer,
pain, systemic absorption, and inammation (edema,
blistering, and crusting)
2.8 MISCELLANEOUS AGENTS
Sunscreens
Sun protection actor (SPF) 5 MED o protected skin
divided by MED o unprotected skin
■
UVB is 10003 more eective at causing erythema than
UVA
■
SPF o 15 blocks 93% o erythematous radiation, while
SPF 30 blocks 97%
■
2 g/cm2 o sunscreen applied in phototesting, but reallie application thickness is lower which reduces
eective SPF
Broad spectrum 5 UVA 1 UVB protection
■
UVA—tanning, photoaging
■
UVB—erythema and DNA damage via pyrimdine dimer
ormation
Water resistant 5 SPF value ater 40 or 80 minutes o water
immersion is the same as the value beore immersion
Chemical absorbers: aromatic compounds that absorb
radiation and convert it into longer, lower-energy
wavelengths
■
UVB: para-aminobenzoic acid (PABA), padimate O,
octinoxate, cinoxate, octisalate, homosalate, trolamine
salicylate, octocrylene, ensulizole
PABA—most potent UVB agent; associated with
contact dermatitis, skin staining; has largely been
replaced by other agents
■
UVA: oxybenzone, sulisobenzone, dioxybenzone,
meradimate, avobenzone, ecamsule
Oxybenzone—contact dermatitis, photoallergy
Avobenzone—photolabile, combined with other
agents to prevent degradation
Physical blockers: chemically inert compounds that
reect/scatter radiation
■
Zinc oxide and titanium dioxide
■
More broad-spectrum coverage (UVA, UVB, and visible
light) → better or patients with photosensitivity
disorders
■
Do not cause contact dermatitis; micronized
ormulations decrease visible light scatter, absorb UV
light and oer improved cosmetic application
AEs: irritation, contact urticaria, irritant contact dermatitis,
allergic and photoallergic contact dermatitis (oxybenzone
is #1 culprit; cinnamates and PABA also common),
photosensitivity, and may ↓vitamin D synthesis
Concurrent administration o DEET (insect repellant) and
oxybenzone may increase absorption o both agents and
reduce SPF
Dihydroxyacetone (ound in sunless tanning products)
has only SPF 4 protection
Window glass absorbs UVB but NOT UVA
Insect repellants (Table 2.9)
Topical cosmetic agents
Bimatoprost
Prostaglandin analog that is approved or eyelash
hypotrichosis (↑ length, thickness, and pigment); AEs
include periorbital skin pigmentation, iris
hyperpigmentation (more common in glaucoma
treatment), and ocular irritation
Brimonidine and oxymetazoline
Topical alpha-adrenergic agonists or treatment o acial
redness in rosacea; ophthalmic oxymetazoline solution is
approved or acquired ptosis
AEs: contact dermatitis, rebound erythema (more so with
brimonidine)
Eornithine
Binds/inhibits ornithine decarboxylase; used in treatment
o emale acial hirsutism; acne is the most common AE
Hydroquinone
Lightens skin color via active reduction o pigment
production (i.e., auto-oxidation o melanin, tyrosinase,
and phenol oxidases into various reactive substances);
competes with tyrosine as substrate or tyrosinase;
production o ROS → melanocyte damage
■
Dermatitis is most common AE; most concerning AEs
are paradoxical hyperpigmentation or exogenous
ochronosis (usually at higher concentrations or longer
time periods); reversible nail discoloration can occur
■
Other bleaching agents: monobenzyl ether o
hydroquinone (potent; used or permanent
depigmentation o normal skin in severe vitiligo), kojic
acid, and mequinol
Psychiatric agents
For a thorough discussion o the subject, we recommend
Journal o the American Academy o Dermatology
2017;76(5):795–808
67
CHAPTER 2 Dermatopharmacology
Table 2.9 Insect Repellants
Insect Repellent
Compound
Synthetic
DEET 5%–100%/5 hours @ 24% Mosquitoes and ticks
Picaridin 7%–20%/8–10 hours @ 20% Mosquitoes and ticks Minor skin irritation/odorless, non-sticky, no harm to
IR3535 7.5%–19.7%/2–3 hours Mosquitoes and ticks Eye irritation/odorless, biodegradable
Natural
Oil o lemon eucalyptus 10%–40%/6 hours Mosquitoes Minor skin irritation
Oil o citronella 0.5%–20%/2 hours Mosquitoes Eye and minor skin irritation
Catnip oil 7%–15%/7 hours Mosquitoes N/A
2-Undecanone 1%–2%/5 hours Mosquitoes and ticks N/A
Only clothing applied
Permethrin 0.5%/6 weeks or re-apply
From Nguyen QD, Vu MN, Hebert AA. Insect repellents: an updated review or the clinician. J Am Acad Dermatol . 2018;S0190-9622(18)32824-X.
Available Concentration/
Average Duration
ater 6 washings
Eicacy Against Mosquitoes
and Ticks Adverse Eects/Special Considerations
Most ecacious insect repellant
Mosquitoes and ticks Eye and skin irritation, neurologic (numbness, tingling,
Urticaria, vesiculobullous skin necrosis at 50%–75% con-
centration, anaphylaxis, cardiovascular (hypotension,
bradycardia), neurologic (lethargy, conusion, headaches, ataxia, disorientation, seizures, tremors)/sunscreen and topical retinoids may increase risk o toxicity. Decreases ecacy o sunscreen. May cause
abric and plastic degradation.
Not recommended or age , 2 months
clothing or plastics
tremors, and at high exposures, paralysis and seizures)/
both an insect repellant and an insecticide
Some classic uses in dermatology include:
■
SSRIs or obsessive compulsive disorders,
trichotillomania, excoriation disorder; associated with
increased suicidal ideation; other AEs include weight
changes, nausea, insomnia and reduced libido
■
Mirtazapine or idiopathic pruritus; AEs: weight gain
and sedation
■
Doxepin or depressed patients with neurotic excoriations
■
Pimozide (low doses o 3–5 mg/day) or delusions o
parasitosis
Antipsychotic (potent centrally acting dopamine
receptor antagonist)
AEs include: extrapyramidal AEs (tardive
dyskinesia—may be irreversible with long-term use,
withdrawal dyskinesia, and akathisia), and cardiac
eects (e.g., arrhythmias rom a prolonged QT
interval)—not typically seen with low doses
■
Atypical antipsychotics (e.g., risperidone, olanzapine,
and quetiapine) or delusions o parasitosis
Dopamine (D2) and serotonin receptor antagonists
Signifcantly ↓ the risk o extrapyramidal AEs (vs.
pimozide)
■
Amitriptyline or nonspecifc cutaneous sensations,
such as burning/stinging/pain
Works as analgesic in this scenario
AEs are anticholinergic, cardiac, sedative, and
orthostatic hypotension (use low doses)
Antiandrogens and androgen inhibitors
Dermatologic uses: hirsutism, acne, and androgenetic
alopecia
AEs: hyperkalemia (typically in patients with renal
insufciency; do not give with agents that ↑ K1 [like
TMP-SMX]), gynecomastia/breast pain, menstrual
irregularities, dizziness, and agranulocytosis (rare); data
does NOT indicate increased risk o estrogen-dependent
malignancies
Theoretical risk o eminization o male etuses i taken
during pregnancy (observed only in animal studies)
Finasteride and dutasteride
MoA: fnasteride is type II and III 5-a reductase inhibitor
(o note, 5-a reductase converts testosterone to
dihydrotestosterone [DHT]) and dutasteride inhibits type
I, II, and III 5-a reductase
Dermatologic uses: androgenetic alopecia (dutasteride
more eective than fnasteride), hirsutism, and
hidradenitis suppurativa
AEs: sexual (↓ libido, impotence, and abnormal
ejaculation), gynecomastia, ↓ PSA, ↓ overall risk o
prostate cancer, and a possible slight ↑ high-grade
prostate cancer and breast cancer; teratogenic (i
pregnant emale is exposed), depression
■
A large randomized controlled trial ound: ↓ overall
risk o prostate cancer, ↓ low-grade prostate cancer, and
slight ↑ high-grade prostate cancer (3.5% vs. 3.0%;
RR 5 1.17); no dierence in mortality between the
fnasteride and placebo groups
Spironolactone
MoA: antiandrogen; blocks androgen receptor →
↓ androgen production; aldosterone antagonist 5 diuretic
properties
68
Combination oral contraceptive pills
MoA: contains both an estrogen and progestin
component, inhibits gonadotropin-releasing hormone
which prevents ovulation. For treatment o acne,
2.8 Miscellaneous Agents
mechanism is based on antiandrogenic properties:
decreases androgen production at the ovary, increases sex
hormone–binding globulin (decreases ree testosterone),
and reduces 5-a reductase activity.
FDA approved or acne: ethinyl estradiol/norgestimate,
ethinyl estradiol/norethindrone, acetate/errous umarate,
ethinyl estradiol/drospirenone, and ethinyl estradiol/
drospirenone/levomeolate
AEs: thromboembolism, stroke (increased risk in age
. 35, cigarette smoking), potential increased risk o breast
and cervical cancer, decreased bone mass
Clascoterone
MoA: topical androgen receptor inhibitor that competes
with DHT or binding androgen receptors within the
sebaceous glands and hair ollicles
FDA approved or acne in ages 12 and older
Vitamin D3 analogs
Calcipotriene and calcitriol
MoA: product binds to vitamin D receptors → drug-
receptor complex 1 RXR-a binds to DNA at vitamin D
response elements → ↓ keratinocyte prolieration/
epidermal dierentiation, ↓ IL-2/IL-6/IFN-g/GM-CSF, ↓
NK-cell and cytotoxic T-cell activity, ↑ involucrin/
transglutaminase → enhanced cornifed envelope
ormation
Dermatologic uses: FDA approved or psoriasis, but used
in morphea and vitiligo; can be used in combination with
5-uorouracil BID 3 4 days or actinic keratoses
AEs: hypercalcemia (uncommon), irritation (most
common), and mild photosensitivity
Attenuated androgens
Danazol and stanozolol
MoA: complex, but involves ↑ production o various
proteins by the liver, including various clotting actors,
inhibitor o frst component o complement (C1 INH),
fbrinolytic proteins
Dermatologic uses: hereditary angioedema (FDA
approved), cryofbrinogenemia, lipodermatosclerosis,
and livedoid vasculitis
AEs: hormonal-related AEs (hirsutism, deeper voice,
alopecia, acne, and menstrual irregularities), muscle
cramps, myalgias, myopathy (in patients on statins),
hematuria/hemorrhagic cystitis, insulin resistance,
headaches, worsening HTN and CHF (drugs retain
sodium), hyperlipidemia, and hepatic AEs (jaundice and
liver tumors)
Contraindicated in childhood and pregnancy
Agents used or anti-infammatory
properties
Cloazimine
Riminophenazine dye used or antibiotic (i.e.,
antimycobacterial, especially multibacillary leprosy
and erythema nodosum leprosum) and anti-
inammatory (e.g., SLE, pyoderma gangrenosum,
erythema dyschromicum perstans, and discoid LE)
purposes
AEs: reversible orange-brown skin and body uid
discoloration, xerosis, and crystal deposition in organs →
enteropathy/splenic inarction/eosinophilic enteritis/
cardiac dysrhythmia
Colchicine
MoA: binds tubulin dimers in leukocytes → mitotic
arrest in metaphase and ↓ chemotaxis
Dermatologic uses: amilial Mediterranean ever
(treatment o choice), neutrophilic dermatoses (e.g.,
Behcet’s disease), cutaneous small vessel vasculitis,
autoimmune connective tissue disorders, and gout
AEs: GI AEs (e.g., cramping, diarrhea, and abdominal
pain, which can → discontinuation); rarely bone marrow
suppression, neuropathy, and myopathy
Nicotinamide (vitamin B3)
MoA: inhibits PARP-1 → ↓ NF-B transcription →
↓ leukocyte chemotaxis; ↓ lysosomal enzyme release;
stabilizes leukocytes by inhibiting PDE →
immunomodulation; ↓ lymphocytic transormation/
antibody production; ↓ mast cell degranulation
Dermatologic uses: pellagra, autoimmune bullous
disorders (in combination w/ tetracyclines), NMSC
chemoprevention
AEs: occasional GI complaints; niacin causes ushing, but
nicotinamide does not
Pentoxiylline
Phosphodiesterase inhibitor that:
■
↑ Erythrocyte/leukocyte deormability
■
↓ Platelet aggregation
■
↓ TNF-a
■
↓ Neutrophil adhesion
Used in Raynaud’s, livedoid vasculopathy, necrobiosis
lipoidica, venous ulcers, and lipodermatosclerosis
AEs are primarily GI; decrease dose in renal dysunction
Potassium iodide
MoA: unknown, likely anti-inammatory (especially
toward neutrophils)
Dermatologic uses: sporotrichosis, erythema nodosum,
and erythema induratum
AEs: hypothyroidism (with chronic high-dose treatment,
mainly in patients with preexisting thyroid issues), chronic
iodine intoxication, skin eruptions (e.g., iododerma,
acneiorm, dermatitis, and vascular), GI AEs (most
common), “iodism” (metallic taste, sore/burning mouth,
and headache), and exacerbation o dermatitis
herpetiormis
Check or thyroid disorders beore starting medication; do
not give large doses during pregnancy (can → goiter/
hypothyroidism in etus)
Tapinaro
MOA: non-steroidal topical aryl hyrocarbon receptor
agonist which decreases IL-17 expression
FDA approved or plaque psoriasis
AEs: olliculitis and contact dermatitis
69
CHAPTER 2 Dermatopharmacology
Thalidomide
MoA: immunomodulatory and antiangiogenic; exact MoA
unknown
■
Anti-inammatory eects: inhibits TNF-a and IFN-g,
↓ IL-12 production, ↓ helper T cells, ↑ suppressor T
cells
Dermatologic uses: erythema nodosum leprosum (FDA
approved), HIV-related disorders, LE, GVHD, prurigo
nodularis (due to neural eects), and neutrophilic
dermatoses (e.g., Behcet’s disease)
AEs: teratogenic (category X—most common deect is
phocomelia), peripheral neuropathy (proximal muscle
weakness 1 distal painul paresthesias/sensory loss),
venous thrombosis, hypersensitivity reaction (more
common in patients with HIV), sedation/drowsiness
(most common), constipation, and various drug
interactions
Topical calcineurin inhibitors
Pimecrolimus and tacrolimus
MoA: bind to FK506-binding protein orming a complex
→ complex binds to enzyme calcineurin → prevention o
calcineurin rom dephosphorylating transcription actor
NFAT-1 → ↓transcription o cytokine IL-2 → ↓T-cell
activation/prolieration
Dermatologic uses: atopic dermatitis (FDA approved),
lichen planus, vitiligo, psoriasis, cutaneous lupus, and
Zoon balanitis
AEs: black box warning or malignancy (likely extremely
low, i any, true risk); be aware o high levels o
absorption in Netherton syndrome; burning sensation
with initial use o tacrolimus
Intravenous immunoglobulin (IVIG)
Comes rom purifed plasma o more than 1000 donors;
contains supraphysiologic IgG primarily
MoA:
■
↓ antibody production
■
↓ complement activation
■
Neutralization o pathogenic antibodies and bacterial
superantigens
■
Binds various immune receptors →
immunomodulation
■
↓ TNF-a and other proinammatory cytokines
■
Antioxidant
■
Blocks Fc receptors
■
↓ T-cell activation through various pathways
■
↑ regulatory T cells
■
Contains anti-Fas receptor antibodies → ↓ keratinocyte
apoptosis
■
↓ migration o immune cells to target tissues
Dose: varies, but generally 1 cycle 5 2 g/kg total, divided
into three doses, with one dose given on each o the 3
consecutive days; usually spaced 2 to 4 weeks apart until
clinical remission, then ↑ intervals thereater
Dermatologic uses: autoimmune blistering disorders,
dermatomyositis, SJS/TEN, Kawasaki disease, SLE,
chronic autoimmune urticaria, scleroderma, and livedoid
vasculopathy
AEs: inusion-related AEs (e.g., headache, myalgia,
ushing, ever, and wheezing; pretreatment with
antihistamines/NSAIDs/CS may help), uid overload
(i.e., in cardiac ailure and renal ailure patients), aseptic
meningitis, thromboembolic events (e.g., MI and stroke;
as a result o ↑ serum viscosity), and dyshidrotic hand
eczema; contraindicated in patients with thimerosal
sensitivity
■
Screen or immunoglobulin levels beore treatment—
patients with IgA defciency may develop anaphylaxis
with treatment
■
Excipients in IVIG may cause renal ailure (i.e., sucrose,
glycine, proline)
Agents or hyperhidrosis
Glycopyrrolate
Anticholinergic agent used orally or topically or
hyperhidrosis
MoA: blocks acetylcholine’s eects on sweat glands
AEs include anticholinergic eects (e.g., dry mouth,
blurred vision, urinary retention), seizures (rare), and
hyperthermia (rare)
Caution with TCAs, atenolol, and digoxin
Oxybutynin
Anticholinergic agent
Approved or overactive bladder but can be used or
hyperhidrosis
AEs: anticholinergic eects
Botulinum toxin
MoA: neurotoxin which binds to SNARE complex on the
presynaptic terminal resulting in blockade o acetylcholine
release
FDA approved or axillary hyperhidrosis
Aluminum chloride
Aluminum salt applied topically plugs the distal
acrosyringium, blocking the output o sweat
AE: dermatitis, irritation
2.9 DRUG INTERACTIONS AND THE CYTOCHROME P-450 SYSTEM
This is a very brie review o drug interactions, mainly as
they relate to cytochrome P-450 (CYP) system
Key points
CYP enzymes metabolize endogenous and exogenous
compounds (e.g., drugs)
Most commonly located in the endoplasmic reticulum o
hepatocytes
Divided into amilies and subamilies based on genetic
similarity
Deects in CYP genes can → altered drug metabolism (e.g.,
CYP2D6 mutations may → poor tolerance to doxepin)
70
2.10 Drug Reactions
Substrate drugs 5 drugs metabolized by a certain CYP
isoorm
■
I given with a drug that inhibits the CYP → ↓
clearance o substrate drug → ↑ levels o substrate drug
and possible toxicity
In this scenario, may need ↓ dose o substrate drug
■
I given with a drug that induces the CYP → ↑
clearance o substrate drug → ↓ levels o substrate drug
and ↓ therapeutic eect
In this scenario, may need ↑ dose o substrate drug
Specic CYP isoorms
CYP1A2
Substrates: theophylline/caeine, wararin, and pimozide
Inhibitors: uoroquinolones, macrolides (e.g.,
erythromycin), and ketoconazole
Inducers: phenytoin, barbiturates, riampin, and cigarette
smoke
CYP2C9
Substrates: phenytoin, sulonamides, wararin, uvastatin,
abrocitinib, and losartan
Inhibitors: uconazole and TMP-SMX
Inducers: carbamazepine and riampin
CYP2D6
Accounts or one-ourth o all drug metabolism
Substrates: TCAs (e.g., doxepin and amitriptyline),
metoprolol/propranolol, antidysrhythmics (e.g.,
encainide and propaenone), antipsychotics (e.g.,
clozapine and pimozide)
Inhibitors: SSRIs (e.g., uoxetine and sertraline),
pimozide, and terbinafne
Inducers: carbamazepine, phenytoin, and riampin
CYP3A4 (most relevant to dermatologists)
Accounts or up to 50% o all drug metabolism
Substrates: many!—wararin, carbamazepine, doxepin,
sertraline, antidysrhythmics (e.g., amiodarone, digoxin,
and quinidine), CCBs (e.g., diltiazem and niedipine),
chemotherapy (e.g., doxorubicin, vinblastine, and
cyclophosphamide), H1 antihistamines, HMG CoA
reductase inhibitors (lovastatin and simvastatin), OCPs/
estrogens, cyclosporine, tacrolimus, CS, dapsone,
pimozide, benzodiazepines, protease inhibitors,
toacitinib, upadactinib, and colchicine
Inhibitors: azole antiungals (e.g., ketoconazole and
itraconazole), clarithromycin/erythromycin,
metronidazole, protease inhibitors, SSRIs (e.g., sertraline),
graperuit juice, cimetidine, and CCBs
■
Important examples: itraconazole given with
cyclosporine → toxicity; same idea i itraconazole given
w/ wararin (→ ↑ anticoagulant potential/INR) or
lovastatin (→ rhabdomyolysis)
■
Azithromycin is NOT a CYP3A4 or -1A2 inhibitor like
other macrolides
Inducers: riampin, griseoulvin, anticonvulsants (e.g.,
phenytoin and carbamazepine), dexamethasone,
eavirenz, nevirapine, and St. John’s wort
■
E.g., riampin given with OCPs → ailure o OCPs
Classic CYP mnemonics
Queen Barbara’s Phenny—she reuses greasy carbs and
alcohol chronically
■
Inducers: quinidine, barbiturates, phenytoin, riampin,
griseoulvin, carbamazepine, chronic alcohol
intake
PICK EGS
■
Inhibitors: protease inhibitors, isoniazid, cimetidine,
ketoconazole, erythromycin, graperuit juice,
sulonamides
2.10 DRUG REACTIONS
Cutaneous drug eruptions (CDEs) are one o the most
common adverse drug reactions; occur in up to 1% o
patients receiving systemic meds
■
Highest risk medications (% on medication that
develop rash): aminopenicillins (up to 8%) .
anticonvulsants (5%) . TMP-SMX (4%) . NSAIDs
(0.5%)
CDEs are divided into simple (no visceral/systemic
involvement) and complex (systemic involvement)
■
2% o all CDEs are SCARs (severe cutaneous adverse
reactions 5 SJS/TEN, DRESS/DHS, AGEP, anaphylaxis,
anticoagulant-induced skin necrosis, and generalized
fxed drug eruption)
SCARs are seen in 1/1000 hospitalized patients
Three most common morphologies: morbilliorm
(.92%) . urticarial (6%) . vasculitis (2%)
Pathophysiology: immunologically mediated
(Table 2.10) (drugs act as haptens inducing
immunologic response) or non-immunologic
(overdose, pharmacologic AEs, cumulative toxicity,
delayed toxicity, drug-drug interactions, alterations in
metabolism, and exacerbation o existing disease)
■
Patch testing may be useul in identiying the
responsible drug in some immunologic reactions such
as fxed drug eruption, AGEP, or symmetrical drugrelated intertriginous and exural exanthema (SDRIFE)
HIV(1) patients have ↑↑ incidence o CDEs
■
Highest risk when CD4 count is 100 to 400/mm
■
Most common: TMP-SMX (rash in 40% o HIV
patients), dapsone, b-lactams, nevirapine, abacavir,
and anticonvulsants
Table 2.10 Immunologic Drug Reactions
Type Mechanism Examples
Type I IgE-dependent Urticaria, angioedema,
Type II Cytotoxic (due to antibodies
directed against ixed
antigens)
Type III Immune complex–dependent Serum sickness, vasculitis,
Type IV Delayed-type/cell-mediated Morbilliorm, ixed drug,
SJS/TEN, Stevens-Johnsons syndrome/toxic epidermal necrolysis.
anaphylaxis
Drug-induced
thrombocytopenia
some urticarias
lichenoid drug, SJS/TEN
3
71
CHAPTER 2 Dermatopharmacology
Morbilliorm (aka exanthematous or
maculopapular drug eruption)
Most common drug reaction aecting skin; mechanism 5
cell-mediated hypersensitivity; onset typically 7–14 days
ater drug initiation
Most common culprit drugs: b-lactams (PCNs and CSNs),
TMP-SMX, anticonvulsants, and allopurinol
Viral inections ↑ incidence o drug reactions:
■
Ampicillin in patients w/ EBV-mononucleosis → rash
in ,100% o children and up to 70% adults
■
Up to 40% o AIDS patients get rash to TMP-SMX
Rash starts w/ red-pink macules/papules in groin/axilla →
later, symmetrically distributed red macules, papules, and
urticarial-like lesions on the trunk and upper extremities →
conuent over time; signifcant pruritus (helps distinguish
rom viral exanthema); spares mucous membranes;
eruption subsides 1 to 2 weeks ater drug cessation
■
Features concerning or SCAR: acial edema or
peripheral eosinophilia (DRESS); mucosal
involvement or dusky/painul skin (early SJS/TEN)
Histopathology: mild basal vacuolar and spongiotic
changes with a ew necrotic keratinocytes (50%),
superfcial to mid dermal perivascular lymphohistiocytic
infltrate with some eosinophils
Rx: supportive, with topical steroids and anti-pruritics;
stop drug usually, but may attempt to “treat through” i
drug is essential (very low rate o progression to SJS/TEN)
Urticaria, angioedema, and anaphylaxis
See Chapter 3.9
Fixed drug eruption/Stevens-Johnson syndrome/toxic epidermal necrolysis
See Chapter 3.3
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS)
Severe systemic drug reaction with 10% mortality
Develops 2–6 weeks ater initiation o drug (later than
other drug reactions)
Most common symptoms 5 ever (85%) and
morbilliorm skin eruption (75%); also see
lymphadenopathy, arthralgias (. arthritis), multiorgan
involvement (Table 2.11) (liver most common [primary
cause o mortality in DRESS], ollowed by kidney),
peripheral eosinophilia (.1500 absolute eosinophils),
mononucleosis-like atypical lymphocytosis
■
RegiSCAR criteria can be helpul (Table 2.12)
Rash starts on ace and upper trunk/extremities; appears
morbilliorm at onset → becomes edematous (acial
edema is classic early clue), with ollicular accentuation
1/– tense vesicles/bullae, pustules, and purpuric lesions
Systemic involvement can persist ater drug withdrawal
Table 2.11 Visceral Involvement in Drug-Induced Hypersensitivity
Syndromes
Medication Clinical Abnormality
Allopurinol Renal
Ampicillin Cardiac
Carbamazepine Renal
Dapsone Hepatic and renal
Minocycline Hepatic, pulmonary, and cardiac
Phenytoin Hepatic
From Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: part I. Clinical
perspectives. J Am Acad Dermatol. 2013;68(5):693.e1–14, quiz 706–708.
Late sequelae: thyroiditis/Graves’ syndrome, SIADH,
myocarditis and diabetes; 10%–20% mortality
Risk actors:
■
Genetic polymorphisms in drug metabolism: inability
to detoxiy arene oxide metabolites (aromatic
anticonvulsants: phenobarbital, phenytoin, and
carbamazepine) or slow acetylator (sulonamides)
■
HLA-A*3101 (Northern Europeans on carbamazepine),
HLA-B-5801 (Han Chinese on allopurinol)
■
Possible role or viral reactivation (HHV-6 or EBV .
HHV-7, CMV)
Most common meds: aromatic anticonvulsants
(phenytoin, carbamazepine, and phenobarbital; all crossreact), lamotrigine (when co-administered with
valproate), sulonamides, minocycline, dapsone,
allopurinol, contrast media, allopurinol, abacavir, and
nevirapine
DIHS variants:
■
Anticonvulsant hypersensitivity syndrome: ↑ risk i
cannot detoxiy arene oxide metabolites; liver
involvement in 70%; less common to have kidney,
lung, or heart involvement; switch to valproic acid or
levetiracetam instead o aromatic anticonvulsants
■
Allopurinol hypersensitivity syndrome: usually seen in
patients with renal ailure; ↑↑ risk or Han Chinese
with HLA-B-5801; liver involvement in 70%; kidney in
up to 80%; also a/w pancreatitis and diabetes; rare to
have lung or lymph node involvement; 25% mortality
■
Sulonamide hypersensitivity syndrome: ↑ risk i slow
acetylator
■
Dapsone hypersensitivity syndrome: concomitant
hemolysis and methemoglobinemia common (due to
dapsone eect) → ↑ bilirubin → icterus;
lymphadenopathy in 80%; lacks eosinophilia; liver
involvement can be atal; ↑ risk in Chinese with
HLA-B*13:01
■
Minocycline hypersensitivity syndrome: typically seen
in young adults undergoing acne treatment; F . M;
a/w glutathione S-transerase defciency; strong a/w
interstitial eosinophilic pneumonia; liver
involvement in 75%; renal involvement in up to 20%
Treatment: discontinue medication, supportive care, and
systemic steroids
■
Relapse common i steroids tapered too rapidly →
usually give or weeks to months
■
Use valproic acid or levetiracetam in place o aromatic
anticonvulsants
72
Table 2.12 RegiSCAR Criteria or Drug-Induced Hypersensitivity Syndrome/
Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)
No Yes Unknown
Fever $ 38.5°C
Enlarged lymph nodes ($2 sites, .1 cm)
Atypical lymphocytes 0 1 0
Eosinophilia 0 — 0
0.7–1.499 3 109/L or 10%–19.9%
$1.5 3 109/L or $20%
Skin rash 0 – 0
Extent . 50%
At least 2 o edema, inltration, pur-
pura, scaling
Biopsy suggesting DRESS –1 0 0
Internal organ involved 0 — 0
1 — 1 —
$2
Resolution in . 15 days
At least three biological investigations
perormed and negative to exclude
alternative
Final score: ,2, no case; 2–3, possible case; 4–5, probable case; .5,
defnite case.
–1 0 –1
0 1 0
– 1 —
— 2 —
0 1 0
–1 1 0
— 2 —
–1 0 –1
0 1 0
Acute generalized exanthematous pustulosis (AGEP)
Acute, ebrile pustular drug eruption that mimics von
Zumbusch pustular psoriasis; occurs rapidly (,4 days)
ater drug administration
Presents with high ever and small (,5 mm) non-
ollicular, sterile pustules arising on the background o
edematous red skin; most commonly begins on ace and
intertriginous sites → generalizes within hours
■
50% o patients have purpuric or EM–like lesions,
mucosal involvement, edema o hands/ace, or bullae
→ these fndings help dierentiate rom pustular
psoriasis
■
↑↑↑ WBC count with peripheral neutrophilia 1/–
eosinophilia, hypocalcemia, and renal insufciency
Patch test positive in majority (50%–60%)
Most common drugs: b-lactam (PCNs and CSNs) and
macrolide antibiotics . CCBs (diltiazem most common)
and antimalarials. Other causes: mercury exposure,
radiocontrast, or enterovirus
Histopathology: subcorneal and intraepidermal
spongiorm pustules with neutrophils, prominent
superfcial dermal edema, and perivascular mixed
inammatory infltrate with neutrophils and eosinophils
■
Presence o edema and eosinophils, and lack o
signifcant acanthosis helps dierentiate rom pustular
psoriasis
Rx: stop drug, supportive therapy with topical steroids and
antipyretics
Photosensitive drug reactions
Due to exogenous photosensitizing agents (meds); may be
either phototoxic (most common) or photoallergic
Phototoxic: common and predictable; occurs in anyone
who receives enough drug and UVR; most commonly due
to systemic meds
2.10 Drug Reactions
■
Mechanism: direct interaction between UVR (UVA
most common) and drug/drug metabolites → ree
radicals → damage to skin cells
■
Presents with painul exaggerated sunburn-like
eruption 1/– blistering within hours → heals with
hyperpigmentation
■
Histopathology (same as sunburn): necrotic
keratinocytes (“sunburn cells”), dermal edema,
minimal dermal inammation, and vasodilation
■
Most common drugs: tetracyclines (demeclocycline .
doxycycline . TCN ». minocycline), NSAIDs
(naproxen and piroxicam), uoroquinolones,
amiodarone, psoralens, phenazothiazines
(chlorpromazine and prochlorperazine), voriconazole
(XP-like presentation w/ ↑↑ risk o aggressive SCC,
eruptive lentigines, premature aging, and early death),
St. John’s wort, EGFR inhibitors, RAF inhibitors, HCTZ,
imipramine
■
Clinical variants:
Pseudoporphyria
♦ Causes: NSAIDs (naproxen is #1), thiazides,
voriconazole, urosemide, TCNs, nalidixic acid,
and tanning bed exposure; may also occur in
hemodialysis patients
♦ Skin fndings similar to PCT, but lacks
hypertrichosis, sclerodermoid eatures, and
hyperpigmentation
♦ Normal porphyrin studies
♦ Histology/DIF: similar to PCT
Photoonycholysis (psoralens and TCNs)
Slate gray hyperpigmentation (amiodarone, TCAs,
and diltiazem)
Photolichenoid eruptions (HCTZ and NSAIDs most
commonly)
UV recall (MTX)
Phytophotodermatitis (urocoumarin-containing
plants 5 parsley, celery, lime, fg, and
yarrow)
Photoallergic: less common, but more chronic than
phototoxic; idiosyncratic; only occurs in sensitized
patients (delayed-type hypersensitivity); oten persists
ater withdrawal o medication; most commonly due to
topical photoallergens
■
Mechanism: cell-mediated hypersensitivity; UVR
(especially UVA) induces chemical change in drug →
becomes photoallergen; requires sensitization with 7-
to 10-day incubation period
■
Presents with itchy, eczematous to lichenoid eruption
on sun-exposed areas initially → later spreads to non–
sun-exposed sites; less likely to be bullous than
phototoxic reactions
■
Histopathology: spongiotic dermatitis, superfcial
perivascular inammation with eosinophils
■
Most common drugs: sunscreens containing
oxybenzone (benzophenone-3) . ragrances (6-methyl
coumarin, musk ambrette, and sandalwood oil),
NSAIDs (piroxicam [patch positive to thimerosal] and
ketoproen), griseoulvin, quinidine/quinine,
sulonamides, and quinolones
■
Diagnosis confrmed by photopatch testing (utilizing
UVA)
73
CHAPTER 2 Dermatopharmacology
■
Drug-induced pigmentary changes
Hyperpigmentation:
■
May be localized or generalized; oten
photodistributed
■
Arises by many mechanisms, including: (1) drug/drug
metabolite deposition; (2) induction o melanin
production; (3) post-inammatory changes due to
photosensitive eruptions
■
Oten a/w melanonychia (longitudinal, diuse, or
transverse) and/or oral pigmentation
■
Most common drugs: minocycline, chemotherapeutics,
and AZT, antimalarials, and heavy metals
■
Usually reversible, but may take months to years
Most common agents: (1) phenols/catechols (includes
hydroquinone, monobenzyl ether o hydroquinone,
various phenol derivatives, and p-cresol); (2)
sulhydryls (includes methimazole); and (3)
miscellaneous drugs (PPD, CS, azelaic acid, benzyl
alcohol, tyrosine kinase inhibitors, mercurials,
arsenic, thiotepa, and physostigmine)
■
Reversible, except monobenzyl ether o
hydroquinone (permanent depigmentation at
application site and distant skin)
Bullous drug reactions, lichenoid drug eruptions, drug-induced connective tissue disease
Hypopigmentation:
■
Most requently due to topical medications, but also
seen with tyrosine kinase inhibitors (imatinib most
commonly; due to inhibition o KIT receptor
inhibition, which is involved in melanogenesis)
■
May be a/w lightening o hair
Table 2.13 Drug Eruptions Not Covered Elsewhere
Drug/Reaction Clinicopathologic Features Most Common Drugs
Skin necrososis
Coumadin-induced skin
necrosis
Heparin-induced
skin necrosis
(heparin-induced
thrombocytopenia with
thrombosis syndrome)
Drug-induced hyperpigmentation
Amiodarone
Anti-psychotics and anti-
depressants
Antimalarials Hyperpigmentation occurs in 25 % o patients taking antimalarials; does not ully
AZT (zidovudine) Widespread mucocutaneous hyperpigmentation (reversible) with accentuation in
Rare, lie-threatening reaction; begins 2–5 days ater drug initiation, when protein
C levels at nadir; ↑ risk in patients with pre-existing protein C deiciency (hereditary
or acquired); initially p/w painul red plaques → hemorrhagic bullae, ulcers on
atty areas (breast, buttocks, thighs); Rx: stop wararin, give vitamin K, heparin, and
IV inusions o protein C; histology: non-inlammatory thrombotic vasculopathy
(multiple ibrin thrombi in dermal/SQ vessels), lacks LCV
Systemic syndrome that p/w ↓ PLT levels, thrombosis and cutaneous necrosis ;
mechanism 5 autoantibodies against heparin/platelet actor 4 complexes →
bound antibodies lead to PLT aggregation and consumption → thrombocytopenia
and clotting (due to PLT aggregates); histology: thrombotic vasculopathy with PLT
aggregates (usually not easily seen on H&E); Rx: stop heparin, start direct thrombin
inhibitor or actor Xa inhibitor
Up to 60% o all patients treated or .3–6 months will develop hyperpigmentation;
most commonly p/w phototoxic eruption (erythema) o ace (.other photoexposed areas) → a smaller subset o cases develop slate-gray discoloration; most
common ater long-term use o amiodarone; hyperpigmentation ades slowly
ater drug d/c; histology: unique appearing yellow-brown granules o lipouscin
(Fontana Masson[1]) in macrophages in perivascular distribution; EM shows lipidlike lysosomal inclusions (unique!)
Progressive blue-gray hyperpigmentation in photo-exposed skin; histology: reractile
golden brown granules (Fontana Masson1, Perls negative) in macrophages in
perivascular distribution
resolve ater drug d/c; histology: deposition o drug-melanin complexes (Fontana
Masson1) and hemosiderin (Perls1) in dermis
Chloroquine/hydroxychloroquine: blue-black to gray hyperpigmentation on pretibial
area (most common presentation, looks identical to type II minocycline
hyperpigmentation o shins) . ace, oral mucosa (subungual and hard palate), sclera
Quinacrine: diuse yellow-brown discoloration o skin and eyes (mimics jaundice)
photo-exposed sites and sites o riction; requent longitudinal melanonychia (.
transverse or diuse); histology: dermal melanophages, ↑melanin in keratinocytes
See Chapter 3.3–3.5
Other drug eruptions
See Table 2.13
Coumadin (occurs in 1/10,000 patients)
Unractionated heparin (. ractionated
LMWH)
Phenazothiazines (thioridazine,
chlorpromazine, promethazine), TCAs
Chloroquine, hydroxychloroquine,
quinacrine
74