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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5192_Библиотеки_им_академика_М_И_Перельмана.pdf
2.5 Oncologic Agents in Dermatology
Small Molecule RTK Inhibitors
EGFR: Eriotinib, Gefitinib, Lapatinib
PDGFR: Imatinib, Cediranib, Dasatinib,
Pazopanib, Sorafenib, Sunitinib, Tandutinib,
Vatalanib, Nilotinib
KIT: Imatinib, Dasatinib, Nilotinib
VEGFR: Pazopanib, Sorafenib, Sunitinib,
Vandetanib, Cediranib, Vatalanib, CHIR-265
RAS
(Active)
Vemurafenib
Dabrafenib
Cl-1040
Selumetinib
Trametinib
RAF
MEK
ERK/
MAPK
GF
Monoclonal Ab Receptor Blockers
VEGFR: Bevacizumab, Ranibizumab
EGFR: Cetuximab, Nimotuzumab,
Panitumumab
Receptor Tyrosine Kinase
Everolimus
Temsirolimus
Rapamycin
mTOR
PIP2
PIP3
AKt
SHh
SMO:
Vismodegib
Sonidegib
SMO
PTCH
SUFU
GLI
GLI1 GLI2 GLI3
GROW T H, S U RVI VA L , PROLI F E R AT I O N
Fig. 2.4 Molecular signaling pathways. Targeted agents listed are meant to be representative and are not intended to be all-inclusive or targeted agent amilies. GF,
Growth actor; RTK, receptor tyrosine kinase; SHh, sonic hedgehog; SMO, smoothened. (Modied rom Macdonald JB, Macdonald B, Golitz LE, LoRusso P, Sekulic
A. Cutaneous adverse eects o targeted therapies. J Am Acad Dermatol. 2015;72[2]:221–236.)
surgery/radiation; may be used in patients with nevoid
BCC syndrome
AEs: muscle spasms, alopecia, dysgeusia, atigue, nausea,
anorexia, and diarrhea
Teratogenic, hedgehog pathway regulates etal
development—contraceptives required or 24 months (F)
and 3 months (M) post-treatment
Verrucous keratosis, warts: most common skin lesion
■
Keratosis pilaris-like eruption
■
Photosensitivity, alopecia, and hyperkeratotic handoot reaction
■
May change preexisting nevi, with possible risk o
melanoma
BRAF blockade in wild-type melanoma may
accelerate cellular prolieration
BRAF inhibitors (vemuraenib,
encoraenib, and dabraenib)
Noncutaneous AEs: arthralgias, panniculitis, nausea,
diarrhea, atigue, QT prolongation, and retinal vein
thrombosis
BRAF: serine/threonine signal transduction kinase important
to the MAPK pathway, which regulates cell division
The most common genetic mutation in melanoma is
V600E mutation (valine replaced by glutamic acid at amino
acid position number 600) o BRAF proto-oncogene; BRAF
inhibitors target this mutation and can increase survival
rates in late stage melanoma
Cutaneous reactions are most common AE:
■
Exanthematous rash—papulopustular on ace, torso,
and arms
■
Keratotic lesions
SCC and keratoacanthoma due to paradoxical
MAP kinase activation keratinocytes (blocked by
addition o a MEK inhibitor)
MEK inhibitors (trametinib, cobimetinib, binimetinib)
Inhibit MEK1/2 o the MAPK pathway
Can be used as monotherapy or in combination with
BRAF inhibitors or late stage melanoma
■
Combination improves efcacy and decreases toxicity
■
↓ SCC risk when MEK inhibitor added to BRAF inhibitor
AEs: morbilliorm eruption, papulopustular eruption,
GI AEs most common (diarrhea, nausea, and vomiting),
hypoalbuminemia, dysgeusia, xerostomia,
cardiomyopathy, interstitial lung disease, and retinal
vein occlusion
55
CHAPTER 2 Dermatopharmacology
Ipilimumab
Fully human monoclonal antibody that binds and inhibits
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) → ↑
T-cell activation against tumor cells (Fig. 2.4)
■
Two signals used or T-cell activation: (1) MHC-TCR
and (2) CD28-B7; CTLA-4 competes with CD28 or B7
binding; CTLA4 is an inhibitor receptor which
downregulates the immune response
Used to treat metastatic melanoma
AEs are called immune-related adverse events:
■
Cutaneous AEs are most common (24%)
Rash (most common): maculopapular or
eczematous on trunk/extremities
Pruritus, alopecia, and hypopigmentation
The development o vitiligo may coner a survival
beneft (suggests inammation targeted towards
melanocytes)
■
GI AEs (most severe issue)
Most common: diarrhea, constipation, and bloating
Most severe: lie-threatening colitis with bowel
peroration
■
Less common: endocrinopathies (hypo/
hyperthyroidism, hypophysitis, adrenal insufciency),
hepatoxicity, pneumonitis, other autoimmune
conditions (myositis, vasculitis, ocular inammation,
myocarditis), neurotoxicity
PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab) and PD-L1 inhibitors (avelumab, atezolizumab)
PD-1 is an immune checkpoint receptor expressed by
activated T cells (see Fig. 2.5)
■
Normally unctions as a “brake” on the immune
response
■
PD-1 on activated T cells binds to its ligands PD1-L1
(B7-H1) and PD1-L2 (B7-DC), which are expressed on
tumor cells → deactivation o T cells → loss o immune
response against tumor
■
Monoclonal antibodies that target PD-1 → prevent
T-cell deactivation → ↑ immune-mediated tumoricidal
activity
Approved or metastatic melanoma
■
Efcacy improved when used in combination with
ipilimumab: 5-year overall survival rate o ipilimumab 1
nivolumab is 52%; main disadvantage 5 ↑ immunemediated AEs
Cemiplimab is FDA approved or metastatic SCC,
advanced BCC not responsive to hedgehog inhibitors;
avelumab and pembrolizumab are approved or Merkel
cell carcinoma
Pembrolizumab is eective or CTCL and Sézary
syndrome
Most common AEs: atigue, rash (pruritic drug eruption)
Other AEs: enterocolitis, endocrinopathies (development
o DM2 thyroiditis, adrenal dysunction) development o
autoimmunity (dermatomyositis, scleroderma, vitiligo,
autoimmune blistering disease), arthralgia, neuropathy,
and renal dysunction/nephritis
AEs have been reported more requently with CTLA-4
inhibitors than with PD-1/PD-L1
Imatinib mesylate
Tyrosine kinase inhibitor
■
Binds to the kinase domain o various tyrosine kinases
(e.g., Bcr-Abl, c-Kit receptor [CD117], and plateletderived growth actor receptor [PDGFR])
Dermatologic applications: melanoma, myeloprolierative
hypereosinophilic syndrome, and dermatofbrosarcoma
protuberans
Cutaneous reactions are common
56
APC
Activation Phase Effector Phase
T cell T cell
APC
T cell
MHC
B7
B7
Anti CTLA-4
lpilimumab
Fig. 2.5 Mechanism o action o immune checkpoint inhibitors.
TCR
CD28
CTLA-4
T cell
TCR
PD-1
Anti PD-1
Pembrolizumab
Nivolumab/Cemiplimab
Tumor
Tumor
cell
MHC
PD-L1
Anti PD-L1
Avelumab
■
Most common: superfcial edema (periorbital edema)
■
Second most common: rash (maculopapular, nonspecifc)
■
Other AEs: hypopigmentation/depigmentation (via
inhibition o c-Kit pathway, which is involved in
melanocyte activation), hyperpigmentation (less
common), lichenoid eruptions (oral and mucosal),
and photosensitivity
Ibrutinib
Selective inhibitor o Bruton’s tyrosine kinase, an enzyme
required or activation o pathways necessary or B-cell
trafcking, chemotaxis, and adhesion
FDA approved or chronic GVHD
AEs: thrombocytopenia, anemia, inection
Talimogene
Engineered oncolytic herpes virus that replicates within
cancer cells, destroying them
FDA approved or injection directly into metastatic
melanoma lesions
AEs: atigue, ever, nausea, u-like symptoms
Mechlorethamine hydrochloride
2.6 Antimicrobial Agents
Most common AE is peripheral neuropathy; other AEs
include atigue and nausea
Mogamulizumab
Antibody against CCR4 (expressed on malignant T cells)
used or relapsed or reractory CTCL
AEs: inusion-related skin eruption, nausea/diarrhea,
thrombocytopenia, dysgeusia, and elevated creatinine.
■
May increase risk o GVHD in allogenic stem cell
transplant recipients
Romidepsin and vorinostat
Histone deacetylase inhibitors used or relapsed or
reractory CTCL
AEs: EKG changes, electrolyte abnormalities, nausea/
dysgeusia, anemia, thrombocytopenia
Topical agents or acitinic keratoses
(AKs) and NMSC (Table 2.6)
2019 NEJM randomized trial or acial AKs showed
5-uorouracil . imiquimod . methyl aminolevulinate
photodynamic therapy . ingenol mebutate
A nitrogen mustard alkylating agent used or patch/plaque
MF; contact dermatitis is the most common AE, but
anaphylaxis and SCC development are the most concerning
Carmustine is also an alkylating agent used or patch/plaque
MF; it can cause severe local reactions and myelosuppression
2.6 ANTIMICROBIAL AGENTS
Topical antibacterial agents
Bacitracin
Brentuximab vedotin
Anti-CD-30 monoclonal antibody used or advanced
CTCL; also used or Hodgkin lymphoma and ALCL
Table 2.6 Topical Treatments or Actinic Keratoses and Non-Melanoma Skin Cancer
Mechanism o Action FDA-Approved Indications Adverse Eects
5-Fluorouracil Antimetabolite/pyrimidine analog which binds to thymidylate
Imiquimod
Dicloenac
Ingenol
mebutate
Tirbanibulin Microtubule inhibitor AKs on ace or scalp Local skin reaction, pruritus, pain
AKs, Actinic keratosis; BCC, basal cell carcinoma; FDA, Food and Drug Administration; GI, gastrointestinal; IFN, intereron; NF-kB, nuclear actor-kB; TNF,
tumor necrosis actor.
synthase (normally converts deoxyuridine → thymidine), and
results in ↓ DNA synthesis
Activator o toll-like receptors 7 and 8 → activation o NF-B
transcription actor → ↑ cytokines/chemokines (e.g., TNF-a
and IFN-g) → innate/acquired immune pathway stimulation
→ antitumor and antiviral activity
Also anti-angiogenic, proapoptotic, and ↑ lymphatic transport
o immune cells/actors → tumor destruction
↓ Cyclooxygenase enzymes → ↑apoptosis
Induces rapid cellular death (within hours) via mitochondrial
swelling/plasma membrane disruption, neutrophil-mediated
antibody dependent cytotoxicity; intense inlammatory
response (within days) via protein kinase C activation
Made by Bacillus subtilis
Bactericidal
Binds to C55-prenol pyrophosphatase → disruption o
bacterial cell wall peptidoglycan synthesis
AKs, and supericial BCCs
(5% strength only)
AKs, supericial BCCs (5%
strength only), and genital/
perianal warts
AKs Mild irritation, rare photosensitivity/
AKs Local reactions (erythema, scaling, and
Local reactions (e.g., erythema, blister-
ing, necrosis, erosions, and burning)
Dihydropyrimidine dehydrogenase de-
ciency can lead to severe toxicity
Local reactions similar to 5-fuorouracil
Flu-like or GI symptoms (especially
i larger areas treated), and psoriasis
exacerbation
photocontact dermatitis; avoid in
patients with NSAID hypersensitivity
and known bleeding diatheses
Pregnancy category B
crusting), which are worse on days 4–7
57
CHAPTER 2 Dermatopharmacology
Activity against Neisseria and gram positives (GPs); poor
activity compared with gram negatives (GNs)
Commonly causes allergic contact dermatitis (especially
common in patients with stasis dermatitis/ulcers)
Polymyxin B
Made by Bacillus polymyxa and B. subtilis
Bactericidal
↑ Cell membrane permeability via detergent-like
phospholipid interaction
Activity against GNs (e.g., Pseudomonas)
Neomycin
Aminoglycoside made by Streptomyces radiae
Binds 30s subunit o bacterial ribosomal RNA →
↓ protein synthesis
Activity against GPs and GNs
Can be combined with bacitracin and polymyxin B (e.g.,
Neosporin)
Common contact allergen, like bacitracin (co-react w/
each other); allergy more common in those w/ stasis
dermatitis and when applied to ulcers; possibility o
ototoxicity/nephrotoxicity but very rare
Mupirocin
Made by Pseudomonas uorescens
Binds to bacterial isoleucyl tRNA synthetase → ↓ RNA/
protein synthesis
Activity against methicillin-resistant S. aureus (MRSA; can
↓ nasal carriage) and Streptococcus pyogenes; resistance has
been reported
Not eective against Pseudomonas (made by Pseudomonas)
Retapamulin
Pleuromutilin made by Clitopilus scyphoides
Binds to L3 protein on 50S subunit o bacterial ribosome
→ ↓ protein synthesis
Activity against MRSA, S. pyogenes, and anaerobes; FDA
approved or impetigo to methicillin-susceptible S. aureus
(MSSA) and S. pyogenes
Can cause contact dermatitis
Gentamicin
Aminoglycoside made by Micromonospora purpurea
Binds to bacterial 30s ribosomal subunit → ↓ protein synthesis
Activity against GPs and GNs (e.g., Pseudomonas)
Silver suladiazine
Binds bacterial DNA → ↓ DNA synthesis; also disrupts
cell walls and membranes
Activity against GPs and GNs, including MRSA and
Pseudomonas aeruginosa
May cross-react with sulonamides; pregnancy category B
Used extensively or burn wounds
Rare AEs include: hemolysis in G6PD patients,
methemoglobinemia, renal insufciency, argyria,
leukopenia, and unmasking porphyria
Iodoquinol
Quinolone derivative with high iodine concentration
Activity against GPs and GNs and dermatophytes/yeasts
Benzoyl peroxide
Broad-spectrum antibacterial agent that unctions via
strong oxidizing properties (good vs. Cutibacterium
acnes)—no bacterial resistance reported to date
Used or acne (alone and in combination with topical
antibiotics and retinoids); has keratolytic properties
When used with certain ormulations o tretinoin, can →
oxidation/degradation o retinoid agent
Most common AE is local irritation; can bleach hair/abric
Metronidazole
Nitroimidazole that disrupts DNA synthesis
Activity against protozoa and anaerobes; not active against
C. acnes, staphylococcus, streptococcus, ungi, or Demodex
Used primarily or rosacea (anti-inammatory properties)
Azelaic acid
Dicarboxylic acid that disrupts mitochondrial respiration,
↓ DNA synthesis (especially in abnormal melanocytes),
and ↓ reactive oxygen species (ROS) production
Also competitively inhibits tyrosinase → ↓ pigmentation
Activity against C. acnes; used in acne and rosacea
(including perioral dermatitis)
May be used in acne and hyperpigmentation disorders (e.g.,
melasma and pregnancy-induced hypertension [PIH])
Sae in pregnancy
Sodium sulacetamide
Activity against C. acnes
Inhibits bacterial dihydropteroate synthetase (prevents
conversion o PABA → olic acid) → ↓ nucleic acid/
protein
Used in acne and rosacea as a combination agent with or
without precipitated sulur
Systemic antibacterial agents
Penicillins
MoA: b-lactam ring binds to bacterial enzyme DD-
transpeptidase → inhibits ormation o peptidoglycan
cross-links in the bacterial cell wall → cell wall
breakdown
Many are susceptible to b-lactamases
Generations
■
First: dicloxacillin, oxacillin
Good or GP cocci, like MSSA
■
Second: aminopenicillins (ampicillin and amoxicillin)
GN bacilli and GP cocci
Amoxicillin has ewer GI AEs
Ampicillin 1 mononucleosis/allopurinol/
lymphocytic leukemia → generalized morbilliorm
itchy eruption starting 1 week ater antibiotic
initiation
May be associated with allergic reactions
■
Third and ourth: carboxypenicillins (carbenicillin) and
ureidopenicillins (piperacillin)
Antipseudomonal activity
■
Combination b-lactam 1 b-lactamase inhibitor
Amoxicillin-clavulanate, ampicillin-sulbactam (IV),
ticarcillin-clavulanate (IV), and piperacillintazobactam (IV)
58
2.6 Antimicrobial Agents
b-lactamase inhibitors inhibit b-lactamase → allows
the b-lactam antibiotic to unction—helpul in
MSSA, Haemophilus, Klebsiella, Escherichia coli,
Proteus, and Bacteroides ragilis inections
Good or polymicrobial inections (e.g.,
amoxicillin-clavulanate is the treatment o choice
or animal or human bites; ticarcillin-clavulanate
good or diabetic oot ulcers and burn wounds)
Ticarcillin/piperacillin → hypernatremia, ↑ LFTs,
neutropenia, and ↑ bleeding times
↑ risk o cholestatic injury with amoxicillin/
clavulanate
Good or various common streptococci (treat b-hemolytic
streptococci or at least 10 days to prevent possible
rheumatic ever) and MSSA skin inections (e.g.,
erysipelas, cellulitis, impetigo, olliculitis, urunculosis,
and ecthyma)
Other uses include staphyloccal scalded skin syndrome
(IV nacillin), syphilis (IM injection o penicillin G),
erysipeloid, cutaneous anthrax, Lyme disease, and
leptospirosis
AEs: hypersensitivity reactions (common association; 2%
o cephalosporin [CSN]-allergic patients are penicillin
[PCN]-allergic), GI AEs (common), hematologic AEs,
shore nails (dicloxacillin), onychomadesis/photoonycholysis (cloxacillin), interstitial nephritis (very rare),
and acute generalized exanthematous pustulosis (AGEP)
Probenecid prolongs renal excretion → ↑ PCN levels
(also can ↑ CSN levels)
Cephalosporins
MoA similar to PCNs as structure is b-lactam ring 1 six-
membered dihydrothiazine ring
Resistant to b-lactamases
Generations
■
First: ceadroxil and cephalexin
Best or GP cocci, but not good or MRSA or PCNresistant Streptococcus pneumonia
■
Second: ceaclor and ceuroxime
More GN activity and less GP activity
Good or Haemophilus inuenzae, Moraxella
catarrhalis, Neisseria meningitidis, and Neisseria
gonorrhoeae
Cephamycins (ceoxitin and ceotetan) are good or
B. ragilis
■
Third: cefxime, cedinir, ceotaxime, cetazidime,
cepodoxime, and cetriaxone
Good GN activity, but not GP activity
Some good or P. aeruginosa (i.e., cetazidime)
Good or sot tissue abscesses and diabetic oot
ulcers
■
Fourth: ceepime (IV)
Broad coverage—MSSA, nonenterococcal
streptococci, and GNs (including P. aeruginosa)
■
Fith: cetaroline (IV)
MRSA S. pyogenes, Streptococcus agalactiae, E. coli, K.
pneumoniae, and K. oxytoca
Acute bacterial skin and sot tissue inections
Oral cephalosporins used requently in dermatology or
uncomplicated skin and sot tissue inections; may need
IV agents or complicated cellulitis or necrotizing asciitis
AEs: GI symptoms (most common), hypersensitivity
reactions (cross-reactivity in ≈ 5%–10% o PCN-allergic
patients), Candida inections, hematologic AEs (e.g.,
hemolytic anemia—ceotetan most common), ↑ LFTs,
serum sickness-like reaction (ceaclor), JarischHerxheimer reaction (in Lyme disease patients receiving
ceuroxime axetil), disulfram-like reaction (ceotetan),
and AGEP
Do not give w/ aminoglycosides → ↑ risk o
nephrotoxicity
Vancomycin
MoA: tricyclic glycopeptide that inhibits bacterial cell wall
synthesis
Only works or GP organisms—most important use in
dermatology is against MRSA skin and sot tissue
inections
AEs: vancomycin inusion (hypersensitivity) reaction,
linear IgA bullous dermatosis (LABD; most common
cause o drug-induced LABD; as a result o IgA antibodies
to LAD285 and IgA/IgG to BP180), hearing loss (patients
with renal ailure), and nephrotoxicity (i given with
aminoglycosides)
Macrolides
MoA: bind to 50S subunit o bacterial ribosome → ↓ protein
synthesis; also has anti-inammatory properties
Good or GPs, except MRSA and enterococcus—used in
dermatology or skin and sot tissue inections
■
Erythromycin
Not used as commonly because o ↑ resistance
(particularly S. aureus) and GI AEs
Some indications include: erythrasma/pitted
keratolysis, anthrax, erysipeloid, chancroid, and
lymphogranuloma venereum (LGV)
May be used or acne, rosacea, and pityriasis rosea
Potent CYP3A4 inhibitor (e.g., monitor use o
wararin, mexiletine, theophylline, and statins
[↑ rhabdomyolysis])
AEs: GI symptoms (most common and dose-
limiting), ototoxicity/hear loss, QT prolongation/
torsades de pointes (worse when given with
terenadine, astemizole, cisapride, and certain
quinolones), and hypersensitivity reactions;
erythromycin estolate in pregnancy may →
hepatotoxicity (intrahepatic cholestasis) in mother;
possible association o cardiovascular malormation
and pyloric stenosis i etus exposed in utero
■
Azithromycin
Better than erythromycin or GPs (→ oten used as
second-line prophylactic antibiotic in dermatology
surgery or PCN/CSN-allergic patients); has some
GN activity (E. coli, N. gonorrhoeae, Haemophilus
ducreyi, and Chlamydia trachomatis)
Activity against Pasteurella multocida (animal bites),
Eikenella corrodens (human bites), and atypical
mycobacteria, Treponema pallidum, Borrelia
burgdoreri (i doxycyline contraindicated),
Toxoplasma gondii, and Klebsiella granulomatis
(granuloma inguinale)
Has been used or acne
59
CHAPTER 2 Dermatopharmacology
AEs: deaness, angioedema, photosensitivity,
hypersensitivity, and contact dermatitis; antacids can
↓ absorption
■
Clarithromycin
Better than erythromycin or GPs
CYP3A4 inhibitor (less potent than erythromycin)
Has activity against some GNs, atypical
mycobacteria (good activity against Mycobacterium.
leprae), T. pallidum, B. burgdoreri, and T. gondii
AEs: metallic/bitter taste, fxed drug eruption,
leukocytolcastic vasculitis (LCV), and
hypersensitivity reactions; contraindicated in renal
dysunction
Fluoroquinolones
MoA: inhibits DNA gyrase (bacterial topoisomerase II)
1/– topoisomerase IV → DNA ragmentation
■
DNA gyrase is predominant target in GN, whereas
topoisomerase IV is target in GP
First- and second-generation quinolones (ciprooxacin,
ooxacin, and nalidixic acid): only target DNA gyrase
(topoisomerase II) → only eective against GN
Third- and ourth-generation quinolones (levooxacin,
moxioxacin, sparoxacin, and gatioxacin): target both
topoisomerase orms (IV . II) → ↑ GP coverage and
↓ bacterial resistance; slightly ↓ efcacy against GN
Ozenoxacin—topical non-uorinated quinolone or
treatment o impetigo
Delaoxacin—new uroquinolone with unique structural
and chemical characteristics; increased potency against
GPs
Good or GNs, like P. aeruginosa (especially ciprooxacin);
may be used with some GPs like S. aureus and S. pyogenes
(primarily third- and ourth-generation quinolones);
ciprooxacin is the treatment o choice or cutaneous
anthrax (B. anthracis); various uoroquinolones eective
or mycobacterial inections
Generally excreted renally, except or moxioxacin
Used in dermatology to treat GN skin and sot tissue
inections, some GP skin/sot tissue inections, GN toe
web-space inections, diabetic oot ulcers, and GN
olliculitis
AEs: GI symptoms (#1), CNS AEs (headache, dizziness,
seizures, psychosis, and depression), tendinitis/tendon
rupture, hypersensitivity (especially ciprooxacin), and
photosensitivity/photo-onycholysis (lomeoxacin,
enoxacin, and sparoxacin .. ciprooxacin .
noroxacin . ooxacin .. levooxacin)
■
Photosensitivity is rom the UVA spectrum (and visible
spectrum or sparoxacin)
■
Levooxacin NOT associated with photosensitivity
Administration with divalent cations (calcium,
magnesium, aluminum, and zinc) → ↓ absorption
CYP1A2 inhibitors (caution with wararin, theophylline,
caeine, anti-arrhythmics [↑ QT/torsades], zileuton, and
beta blockers); also caution with cyclosporine (in setting
o organ transplant, can → ↑ creatinine levels)
Tetracyclines
MoA: binds 30s subunit o bacterial ribosome →
↓ protein synthesis; anti-inammatory properties (e.g.,
inhibits multiple matrix metalloproteinases, neutrophil
migration, and ↓ innate cytokines)
Main uses in dermatology: acne, perioral dermatitis,
rosacea, bullous pemphigoid, conuent and reticulated
papillomatosis (CARP; minocycline), cutaneous
sarcoidosis/other granulomatous diseases (minocycline),
acne keloidalis nuchae, PLEVA/PLC, and acneiorm
eruptions 2° to epidermal growth actor receptor
(EGFR) inhibitors
■
Sarecycline—narrow-spectrum tetracycline developed
or acne only; limited activity against bowel ora, less
GI upset, less photosensitivity
Also useul or various GP and GN skin inections,
including MRSA (doxycycline and minocycline) and those
caused by Chlamydia spp. (doxycycline is the treatment
o choice in LGV), Rickettsia spp. (doxycycline is the
treatment o choice or rickettsial and rickettsial-like
inections—Rocky Mountain spotted ever (RMSF),
rickettsialpox, Q ever, trench ever, and ehrlichiosis),
Mycoplasma spp., atypical mycobacteria, spirochetes
(syphilis [i patient is PCN-allergic], and Lyme disease—
doxycycline is the treatment o choice in early disease)
■
Subantimicrobial doses, (,50 mg, or extended
release) eective or rosacea and acne, and do NOT
↑ bacterial resistance; may also have ↓ rate o vaginal
candidiasis
■
Bacterial resistance via ribosomal protection and/or
drug eux
■
Lipophilic (minocycline . doxycycline . tetracycline)
■
Food decreases absorption, more so in tetracycline
than in doxycycline or minocycline
■
Various metallic cations (e.g., calcium, iron, zinc,
magnesium, bismuth, and aluminum) can ↓
absorption via chelation (tetracycline . doxycycline .
minocycline)
Found in products like antacids, laxatives, dairy, and
supplements
AEs: GI symptoms (esophagitis, nausea, and abdominal
pain; most common with doxycycline, but less so with
enteric-coated orm), acute vestibular AEs (dizziness and
vertigo; usually with minocycline), benign intracranial
HTN/pseudotumor cerebri (usually minocycline; ↑ risk i
given w/ isotretinoin), photosensitivity/photo-
onycholysis (demeclocycline . doxycycline .
tetracycline . minocycline), hyperpigmentation o skin/
nail beds/teeth/mucous membranes/bone (minocycline),
vaginal candidiasis, GN acne/olliculitis, serum sicknesslike reactions (minocycline), drug-induced Sweet’s
syndrome (minocycline), autoimmune hepatitis
(minocycline), DRESS/DHS (minocycline), lupus-like
syndrome (minocycline; usually ANA1, may be antihistone 1 or –), and cutaneous PAN/vasculitis
(minocycline; pANCA1)
■
Minocycline hyperpigmentation types:
Type 1: Blue-gray in sites o acial scarring—stains
or iron and melanin
Type 2: Blue-gray on shins and/or orearms—stains
or iron and melanin
Type 3: Diuse muddy brown on sun-exposed
skin—stains melanin only; represents a low-grade
phototoxic eruption with PIH
60
2.6 Antimicrobial Agents
Tetracyclines are unsae in pregnancy → aect etal teeth/
bones
Do not give to patients under 8 years old → tooth
discoloration
■
Tetracycline and minocycline can also induce adultonset tooth pigmentation
Severe rickettsioses (RMSF) are the exception or
treating children with tetracyclines
Tetracyclines excreted renally, except doxycycline (mainly
via GI tract—so can be used in renal ailure)
Riampin
MoA: binds b-subunit o bacterial DNA-dependent RNA
polymerase → ↓ RNA/protein synthesis
Eective against various mycobacteria (e.g.,
Mycobacterium tuberculosis, M. leprae, and Mycobacterium
marinum) and some other GP and GN organisms (e.g.,
staphylococcus)
■
Single-agent riampin is an eective treatment agent
or latent TB; also used in combination with other
antimicrobials due to rapid development o
resistance
Major CYP450 inducer → ↑ drug clearance/↓ efcacy
(e.g., oral contraceptive pills [OCPs], wararin, azoles,
CCBs, statins, and cyclosporine)
Dermatologic uses: mycobacterial inections (part o
multidrug therapy), Bartonella inections (e.g., cat-scratch
disease and bacillary angiomatosis), MRSA/MSSA,
rhinoscleroma, and cutaneous leishmaniasis; also used in
combination with clindamycin or hidradenitis
suppurativa
AEs: orange-red discoloration o body uids, CNS
(headache and drowsiness), GI symptoms, development
o riampin-dependent antibodies (can → anaphylaxis,
u-like symptoms, renal ailure, and hemolytic anemia),
hepatotoxicity (especially w/ isoniazid), DVTs, pulmonary
fbrosis, ocular AEs, worsening o porphyria (induces
d-aminolevulinic acid [(ALA] synthase), and possible
hemorrhagic disease o the newborn and mother in
pregnancy
Trimethoprim-sulamethoxazole (TMP-SMX;
cotrimoxazole)
Dihydroolate reductase inhibitor (trimethoprim) 1
dihydropteroate synthase inhibitor (sulamethoxazole)
→ ↓ tetrahydroolic acid → ↓ bacterial nucleic acid/
protein synthesis
Eective against various GP cocci (e.g., MRSA, Enterococcus
aecalis, and S. pyogenes), H. inuenzae, P. jirovecii, Nocardia
spp., Chlamydia, and various GNs
Dermatologic uses: acne, hidradenitis suppurativa,
granuloma inguinale, actinomycetoma, cat-scratch
disease, and chronic melioidosis (Burkholderia
pseudomallei)
Caution in patients w/ renal insufciency as it is primarily
renally cleared
AEs: most commonly GI and CNS, but also antibiotic-
associated colitis, hypersensitivity reactions (cutaneous
eruptions much more common in HIV patients; TMP-SMX
accounts or 30% o SJS/TEN cases), hematologic AEs
(agranulocytosis, thrombocytopenia, olate defciency 1
megaloblastic anemia, neutropenia, and hemolytic
anemia in patients w/ G6PD defciency)
May not be sae in pregnancy—sulamethoxazole can
result in jaundice, hemolytic anemia, and kernicterus o
baby i taken in third trimester
Can ↑ dapsone levels, ↑ hematologic toxicity in
patients taking MTX (both ↓ tetrahydroolate), ↑ renal
toxicity in patients taking cyclosporine, ↑ K1 in patients
on ACEIs/ARBs
Clindamycin
Lincosamide that binds to 50S subunit o bacterial
ribosomal RNA → ↓ ribosomal translocation/protein
synthesis
Eective against GP cocci (e.g., Staphylococcus spp. and
Streptococcus spp.) and anaerobes (Bacteroides spp. and
Clostridium perringens), but not usually GNs (except
Capnocytophaga canimorsus)
■
“D zone” test helps determine whether inducible
resistance is present in an erythromycin-resistant,
clindamycin-sensitive organism (bacteria with erm
gene)
Dermatologic uses: skin and sot tissue inections (e.g.,
staphylococci, MRSA, and MSSA), including some deep
sot tissue inections (e.g., streptococcal myositis, C.
perringens inection, and diabetic oot ulcers); acne;
hidradenitis suppurativa (with riampin)
AEs: antibiotic-associated colitis, rashes, and rare
bone marrow suppression may ↑ neuromuscular
blocking
Carbapenems
MoA: similar to other beta-lactam antibiotics but diers
by addition o a double bond to the 5-membered ring o
the penicillin nucleus and the substitution o a sulur
atom by a carbon atom
Agents include imipenem (ormulated with cilastin to
protect kidney against nephrotoxicity), ertapenem,
doripenem, meropenem; all are administered
parenterally
Good or multidrug-resistant bacterial inections, and
have a broad spectrum o activity (GN bacteria, GP
bacteria, aerobes and anaerobes)
Typically not highly active against MRSA and CNS but can
be used in mixed ora inections (e.g. decubitus ulcer/
diabetic oot ulcer) and skin/sot-tissue inections resistant
to other agents; imipenem also used in acute ares o
severe hidradenitis suppurativa
AEs: may have cross sensitivity in those with PCN
allergies, seizures (imipenem . meropenem), nausea/
vomiting, LFT elevation, leukopenia, severe allergic
reactions, hypersensitivity reactions, Clostridium difcile
colitis
Linezolid
MoA: binds 23S portion o 50S ribosomal subunit o
bacteria
Good or skin inections caused by staphylococcus
(including MRSA) and streptococcus
Typically not frst line, but good or resistant cases
61
CHAPTER 2 Dermatopharmacology
AEs: myelosuppression in 2%, serotonin syndrome (i
given with serotonergic drugs like selective serotonin
reuptake inhibitors [SSRIs], monoamine oxidase inhibitor,
and tricyclics), and optic/peripheral neuropathy
Quinupristin and dalopristin
MoA: diuses through bacterial cell wall and binds 50S
ribosomal subunit sites → ↓ protein synthesis
Used in complicated skin and sot tissue inections caused
by GPs (e.g., MRSA and vancomycin-resistant enterococci
[VRE])
AEs: anaphylaxis, angioedema, and ↑ bilirubin
Potent CYP3A4 inhibitor
■
Probenecid → ↑ bioavailability and ↓ renal clearance
I viral resistance occurs (via mutations in thymidine
kinase, or less commonly in DNA polymerase) → use
oscarnet or cidoovir
■
Patients resistant to acyclovir will also be resistant to
valacyclovir, amciclovir, and penciclovir
Valacyclovir
Prodrug o acyclovir with greater bioavailability (almost as
much as IV acyclovir); oral and topical orms
Same uses as acyclovir with excellent AE profle and easier
dosing
■
Rarely can cause TTP/HUS in HIV patients
Daptomycin
MoA: depolarizes bacterial cell membrane → cell death
Good or complicated skin and sot tissue inections caused
by GPs (e.g., MRSA, VRE, and linezolid-resistant GPs)
AEs: neuropathy, myopathy (check CPKs; caution w/
statins), eosinophilic pneumonia, and nephrotoxicity
Others
Some new antibiotics or complicated skin inections
include: telavancin, tigecycline, tedizolid, ozenoxacin,
cetaroline osamil, omadacycline, dalbavancin, and
oritavancin
Antiviral agents
Acyclovir
Guanosine analog that requires:
■
Phosphorylation frst by herpes-specifc thymidine
kinase → acyclovir monophosphate
■
Subsequent phosphorylation by human cellular GMP
kinase and other cellular kinases → acyclovir
triphosphate
At this stage, it competes with deoxyguanosine
triphosphate as a substrate or viral DNA
polymerase → incorporates into viral DNA → chain
terminates and ↓ viral duplication
Penciclovir also works in this ashion
Valacyclovir and amciclovir are prodrugs o (and
converted to) acyclovir and penciclovir, respectively,
so they are also dependent on these enzymes and
pathways
Topical and systemic orms available; considered sae in
pregnancy
■
Topical orm only approved or HSV, not varicella
zoster virus (VZV)
Dermatologic uses: HSV inections, VZV, and recurrent
erythema multiorme (EM) 2° to HSV
■
Consider suppressive doses in HSV patients i more
than six outbreaks per year
■
IV orm used in cases o disseminated HSV/VZV,
eczema herpeticum, and in immunosuppressed
patients
Low rate o AEs and interactions:
■
IV inusions rarely associated with renal impairment
(2° to crystalline nephropathy)
■
Zidovudine (AZT) 1 acyclovir can → drowsiness/
lethargy
Famciclovir and penciclovir
Famciclovir is a prodrug o penciclovir
■
Famciclovir is available orally, but penciclovir only
available topically
■
Penciclovir triphosphate has signifcantly longer hallie than acyclovir triphosphate
■
Famciclovir has even better bioavailability than
valacyclovir
■
Famciclovir and valacyclovir more eective at ↓ VZV
pain than acyclovir
■
Indications:
Famciclovir: same indications as acyclovir/
valacyclovir
Penciclovir: herpes labialis only
Cidoovir
Nucleoside phosphate analog o deoxycytidine
monophosphate eective in HPV, HSV, cytomegalovirus
(CMV) retinitis (“Cidoovir 5 CMV”), or, and
molluscum
■
Must be phosphorylated twice, to cidoovir
diphosphate, in order to be active
■
Does NOT require viral thymidine kinase
■
Once active, acts as a competitive inhibitor and
alternate substrate or viral DNA polymerases →
incorporates into DNA strand → blockage/termination
o DNA synthesis
IV and topical orms available (topicals are not
commercially available, however)
AEs: nephrotoxicity (most common), neutropenia,
alopecia, uveitis/iritis, and cardiomyopathy
Foscarnet
A pyrophosphate analog that binds to pyrophosphate-
binding site on viral DNA polymerase → inhibition o
pyrophosphate cleavage rom deoxyadenosine
triphosphate → disruption o DNA elongation
Treatment o choice or acyclovir-resistant HSV (does
not require same enzymes as acyclovir and penciclovir);
also used to treat CMV retinitis and CMV skin inection in
HIV patients
AEs: penile erosions, thrombophlebitis, nephrotoxicity,
seizures, and electrolyte disturbances
Bleomycin
Chemotherapeutic agent that can be used intralesionally
or warts
62
MoA: binds DNA → single strand breaks → ↓ protein
synthesis → ↑ apoptosis/necrosis o keratinocytes
AEs: injection pain, Raynaud’s phenomenon, loss o nail
plate/nail dystrophy, and agellate hyperpigmentation
Podophyllin resin and podophyllotoxin
Podophyllin administered in ofce and its derivative
podophyllotxin administered at home by patient
■
podophyllotxin is saer—ewer mutagens
Antimitotic agent that binds tubulin → cell cycle arrest in
metaphase
FDA approved or genital warts
AEs are typically local (contraindicated in pregnancy—
teratogenic)
Cantharidin
Blistering agent (comes rom blister beetle/Spanish y,
Lytta vesicatoria)
MoA: disrupts desmosomes → intraepidermal
acantholysis → bullae
Applied in ofce under occlusion or warts/molluscum;
washed o at home 4 hours later
AEs: pain rom blister and ring wart ormation
Sinecatechins
Green tea (Camellia sinensis)–derived polyphenol
epigallocatechin gallate → apoptosis, inhibition o
telomerase, and an antioxidant eect on cells
Approved or genital/perianal warts; AEs are local (e.g.,
pain, itch, and swelling)
5-Fluorouracil and imiquimod (discussed in section 2.5)
Antiungal agents
I. Azoles
MoA: inhibit 14a demethylase (catalyzes conversion o
lanosterol to ergosterol) → ↓ ergosterol → ↓ cell
membrane synthesis, ↑ membrane rigidity/permeability,
growth inhibition, and cell death
Itraconazole
Metabolized mainly in liver (CYP3A4); absorption
enhanced in an acidic environment
FDA-approved indications: dermatophyte onychomycosis
(200 mg BID once a week or 2 months or fngernails
and 200 mg daily or 12 weeks or toenails),
oropharyngeal/esophageal candidiasis, blastomycosis,
histoplasmosis, and aspergillosis reractory to
amphotericin B
O-label dermatologic uses: other tinea inections,
Candida inections, extensive tinea versicolor (or
very short courses or even single doses), and
nondermatophyte/saprophytic onychomycosis.
Contraindications:
■
Ventricular dysunction and CHF
■
Active liver disease or h/o liver toxicity with other drugs
■
Concurrent use o certain drugs metabolized via
CYP3A4 (e.g., pimozide, quinidine, and cisapride) as
it is a CYP3A4 inhibitor
2.6 Antimicrobial Agents
■
Concurrent use with levomethadyl, doetilide, statins,
midazolam, triazolam, nisoldipine, and ergot
alkaloids
Common AEs: GI (e.g., nausea, vomiting, and abdominal
pain), cutaneous (e.g., rash—more common i also using
immunosuppressive meds), neurologic (e.g., headache),
edema, ↑ LFTs, rhinitis, and ever
Rarer AEs: hearing loss, peripheral neuropathy, CV events
(e.g., CHF), dysgeusia, pancreatitis, hepatotoxicity,
neutropenia/leukopenia, pulmonary edema, and
hypokalemia
Fluconazole
Very little hepatic metabolism; pregnancy category D
Unlike itraconazole, absorption not dependent on ood
or gastric pH
FDA approved or vaginal/oropharyngeal/esophageal
candidiasis and cryptococcal meningitis
O-label dermatologic uses: tinea inections,
systemic Candida inections, cutaneous candidiasis,
coccidioidal meningitis, and onychomycosis due to
dermatophyte and non-dermatophyte (e.g.
Scopulariopsis and Candida) (150–300 mg once a
week or 6–9 months in ingernails and 12–18
months in toenails)
Contraindications:
■
Potent CYP2C9 inhibitor – caution with substrates
■
Do NOT administer with pimozide, quinidine,
cisapride, erythromycin, terenadine, astemizole,
voriconazole, or statins
Common AEs: GI (e.g., nausea and abdominal pain), skin
rash, and headache
Rare AEs: CV events (e.g., torsades), cholestasis/
hepatocellular damage/liver ailure, severe skin reactions,
seizures, leukopenia/thrombocytopenia, dysgeusia, and
hyperlipidemia
Ketoconazole
Systemic orm not commonly used because o the
associated high rate o hepatic toxicity
FDA approved or tinea corporis/cruris/pedis/capitis,
chronic mucocutaneous candidiasis, vaginal and
cutaneous candidiasis, chromoblastomycosis,
blastomycosis, histoplasmosis, coccidioidomycosis, and
paracoccidioidomycosis
Topical uses: tinea inections, cutaneous candidiasis, tinea
versicolor, and seborrheic dermatitis
Do NOT administer with cisapride, terenadine, or
astemizole, as interaction can → serious CV events like
↑ QT syndrome
AEs (systemic orm only): GI symptoms, idiosyncratic
adrenal suppression, pruritus, and urticaria
Voriconazole
New generation o azoles used primarily or serious,
invasive ungal inections in immunosuppressed hosts
(invasive aspergillosis, Candida inections, and Fusarium
inections)
Unique AEs: severe phototoxicity (including
pseudoporphyria, and xeroderma pigmentosum [XP]-
like changes) and ↑ risk SCC, visual disturbances (e.g.,
63
CHAPTER 2 Dermatopharmacology
blurriness), hepatotoxicity, GI issues, and QT
prolongation
Posaconazole
Triazole aniungal (similar to itraconazole), used or
invasive Aspergillus and Candida inections in
immunocompromised patients
AE: ever, diarrhea/nausea/vomiting, CYP3A4 inhibitor,
LFT elevations
Miconazole, clotrimazole, and econazole
Topical azoles active against various dermatophytes,
Malassezia urur, and Candida albicans
Good or tinea inections, tinea versicolor, and cutaneous
candidiasis
Efnaconazole
Solution triazole or onychomycosis—daily 48-week
course 15%–20% complete cure; AEs: ingrown toenail,
application site dermatitis
Luliconazole
Once-daily 1% cream used or cutaneous dermatophyte
inections
Other topical antiungals good or cutaneous
dermatophyte inections and possibly cutaneous Candida
inections include oxiconazole, sulconazole, and
sertaconazole
II. Allylamines/benzylamines
MoA: inhibit squalene epoxidase (catalyzes conversion o
squalene to lanosterol) → ↓ cell membrane synthesis
Terbinafne
Oral and topical ormulations
Metabolized mainly in liver—do NOT give in active liver
disease; also do not give i CrCl # 50 mL/min
FDA approved or dermatophyte onychomycosis and tinea
capitis (granule ormulation)
O-label dermatologic uses (systemic ormulation): other
tinea inections, subcutaneous/systemic mycoses (e.g.,
histoplasmosis and chromoblastomycosis), and other
types o onychomycosis (good or Aspergillus, but not
Candida)
Topical ormulation: utility limited to superfcial
dermatophyte inections
■
More eective than clotrimazole and oxiconazole or
tinea pedis
6-week 250 mg/day course or fngernail onychomycosis
and 12-week 250 mg/day course or toenail
onychomycosis (clinical cure ≈ 60%–70%)
Tinea capitis:
■
Highly eective against endothrix organisms (most
commonly Trichophyton tonsurans)
■
Less eective against ectothrix organisms like
Microsporum canis (griseoulvin preerred)
Most common AEs: GI (e.g., diarrhea), cutaneous (e.g.,
rash), headache, and ↑ LFT
Rarer AEs: taste/smell disturbance, severe skin reactions
(e.g., SJS/TEN), visual disturbance, hepatobiliary
dysunction/hepatitis/liver ailure (idiosyncratic),
hematologic abnormalities (e.g., neutropenia or
thrombocytopenia), rhabdomyolysis, depression,
exacerbation o SLE, drug-induced subacute cutaneous
lupus (SCLE)
Inhibits CYP2D6, so exercise caution i giving with
CYP2D6 substrates (e.g., doxepin or amitriptyline)
Natifne
Topical eective or dermatophyte inections primarily
(may be more eective than azoles in treatment o
cutaneous dermatophytoses)
Butenafne
Benzylamine class topical antiungal eective in cutaneous
dermatophyte inections, tinea versicolor, and cutaneous
candidal inections
III. Griseoulvin
MoA: intereres with tubulin → inhibition o mitosis;
binds to keratin in keratin precursor cells → resistance to
ungal inections
FDA approved or dermatophyte onychomycosis and tinea
corporis/cruris/pedis/capitis
■
More eective than terbinafne in tinea capitis caused
by Microsporum (e.g., M. canis)
AEs: GI disturbance and headache are most common;
fxed drug eruption, photosensitivity, and exoliative
dermatitis; can instigate or worsen porphyria and
lupus
IV. Ciclopirox olamine
MoA: disrupts ungal cell membrane transport o
important molecules, ↓ cell membrane integrity, inhibits
cellular respiratory enzymes, and blocks important
enzymatic coactors
Topical cutaneous dermatophyte inections, Malassezia
spp., tinea versicolor, cutaneous candidiasis, and
onychomycosis (in lacquer orm)
■
Ciclopirox and topical azoles are superior to
allylamine/benzylamine drugs or Candida
V. Selenium sulde
Topical cytostatic eect on epithelium, diminishing the
ormation rate o the stratum corneum—treats tinea
versicolor, seborrheic dermatitis o scalp, and CARP
VI. Nystatin
Polyene topical agent that binds Candida cell membrane
sterols → ↑ permeability → cell death
Used or cutaneous/mucosal Candida inections
VII. Echinocandins (caspoungin,
micaungin, and anidulaungin)
MoA: inhibit b-(1,3)-D-glucan synthase → ↓ glucan
production → disrupt cell wall synthesis
64