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1.7 Laboratory Techniques
A
Antigen
Primary antibody
Secondary antibody
Fig. 1.19 Schematic diagram of immunohistochemical techniques. (A) Direct method: the antigen-specic primary antibody is biotin labeled. Biotin binds to avidin/
streptavidin. Color visualization is achieved through enzymatic reaction of horseradish peroxidase/alkaline phosphatase. (B) Indirect method: the antigen-specic primary antibody is unlabeled. The secondary, biotin-labeled antibody binds to primary antibody. Visualization is achieved accordingly through avidin/streptavidin and
peroxidase/alkaline phosphatase complexes. The indirect method increases versatility because unlabeled primary antibodies can be used. (C) Indirect method with
polymer chain detection system. Biotin and avidin/streptavidin are replaced by a labeled polymer chain, allowing for increased sensitivity and specicity. (From Schacht
V, Kern JS. Basics of immunochemistry. J Invest Dermatol. 2015;135(3):1–4.)
can be quantied by a plate reader) and the level of
autoantibody measured.
• Variations/alternatives: IIF (see above) is an alternative to
this method, and Western blot is another way to detect
proteins in a sample. In this method, the antigen is run
on a gel and precipitated on a membrane; binding of the
antibody is then visualized similarly to ELISA. Western
blot is somewhat less quantitative than ELISA but can
provide information about the size of an antigen and
conformation in the sample. Mass spectrometry is a
technique used mostly in research to measure the precise
size of the mass of proteins or peptides. Usually the
proteins are rst separated by electrophoresis to simplify
the sample. Mass spectrometry is then performed by
ionizing the peptides and then measuring the time of
ight of these charged ions. By calculating the peptide
mass/charge ratio, the sequence of the peptide can then
be identied.
1.7.3 Cellular engineering and gene therapy
• Skin’s accessibility provides a unique opportunity for
therapies that aim to restore or repair skin structure and
function via genetic manipulation. This approach,
historically termed “gene therapy,” is now encompassed
under the umbrella of genetic and cellular engineering.
• Although these approaches remain in the research stage,
there are already case reports of successful treatment of
genetically based diseases such as epidermolysis bullosa
• Due to risks and challenges involved in genetically
manipulating cells in vivo (e.g., requirement of injecting
material to transform cells, limited durability of gene
expression, and oncogenic potential), most approaches
rely on harvesting cells from a patient, genetically
B
C
Biotin
Avidin/streptavidin
Peroxidase/
alkaline phosphatase
manipulating them ex vivo and then re-delivering them as
therapy. This can be done in theory for keratinocytes,
induced pluripotent stem (iPS) cells, and immune cells
among other types. For keratinocytes, cells are often
differentiated in vitro to more closely resemble a functional
epidermis before grafting back onto the patient.
• In cases where a gene is mutated or absent, the usual
strategy is to transform cells with a viral or non-viral vector
that contains a functional copy of the gene. The DNA
transposon Sleeping Beauty is an example of a non-viral
vector that will incorporate randomly into the genome.
However, it could do so at an inopportune location,
activating a proto-oncogene. Viral vectors include selfinactivating lentiviral and gamma retroviral vectors.
Limitations of these include broad tropism for many cell
types, limited DNA packaging capacity and immunogenicity
(i.e., development of an immune response against elements
of the viral DNA; an immune response to the corrected
protein is a potential caveat to any approach).
• An alternative approach to providing a second functional
copy of a gene is to repair it in its endogenous location in
the genome. More recently developed technologies, in
particular CRISPR/cas (Fig. 1.20), but also zinc-nger
nucleases and transcription activator-like effector
nucleases, have enabled this by being able to introduce
double-stranded DNA breaks in a specic location
anking the gene of interest. If a copy of the gene with the
correct sequence and anking DNA outside the area of the
induced breaks is then provided via a plasmid, the gene is
then repaired via homologous recombination.
• Finally, in situations where production of an aberrant
protein has a dominant-negative effect, the better
approach might be to suppress expression of the gene via
elimination of mRNA. Here, there are also various options
as outlined in Fig. 1.21
35
CHAPTER 1 • Basic Science
Target DNA
sgRNA
Cas9
PAM sequence
Non-homologous end joining
Homology-directed repair
Point mutation
Site-specific DNA break
Donor DNA
Corrected
nucleotide
Nucleotide deletion
Precise repair
Nucleotide insertion
Gene disruption
Fig. 1.20 Clustered regularly interspaced palindromic repeats (CRISPR)-induced nonhomologous end-joining (NHEJ) and homology-directed repair (HDR). Upon
CRISPR-associated protein 9 (Cas9)-induced DNA double-stranded break (DSB), the cell repairs the DSB by either NHEJ or HDR. In NHEJ, random nucleotide insertions and deletions occur as the cell ligates the DNA DSB, resulting in gene disruption. In HDR, the DSB is repaired using an externally supplied homologous DNA as
a template for copying. The nucleotide sequence of the donor template is copied into the targeted site, resulting in a directed precise repair. PAM, Protospacer adjacent
motif; sgRNA, single-guide RNA. (From Guitart JR Jr, Johnson JL, Chien WW. Research techniques made simple: the application of CRISPR-Cas9 and genome editing in investigative dermatology. J Invest Dermatol . 2016;136(9):e87–e93; Adapted and modied from Savic´ N, Schwank G. Advances in therapeutic CRISPR/Cas9
genome editing. Transl Res. 2016;168:15–21.)
36
1.7 Laboratory Techniques
MECHANISMS OF SEQUENCE-SPECIFIC GENE SILENCING VIA mRNA KNOCKDOWN
A
Chemically synthesized
short interfering RNA
(siRNA) molecule
5 AAA3
mRNA cleavage
Short hairpin RNA
(shRNA) precursor
expressed from plasmid
or viral vector DNA
5
3
shRNA
5 3
3 5
siRNA
3 5
siRISC
B
Dicer
Duplex unwinding
and strand selection
AAA
C
MicroRNA (miRNA)
precursor expressed
from genomic DNA
Processing and
export from nucleus
5
3
pre-miRNA
5 3
3 5
miRNA
5 AAA3
Ribosome
3 5
miRISC
Dicer
mRNA degradation
Fig. 1.21 Mechanisms of sequence-specic gene silencing via mRNA knockdown. (A) Short (small) interfering RNA (siRNA) is unwound and the “guide” antisense
strand incorporated into an RNA-induced silencing complex (RISC) that degrades a specic target mRNA sequence. Processing short hairpin RNA (shRNA); (B) and
pre-microRNA (miRNA); (C) by the Dicer enzyme can generate siRNA and miRNA, respectively. (C) Endogenously produced miRNA regulates up to a third of human
genes and tends to have less complementarity with target mRNA; it recruits RISC proteins and typically inhibits mRNA translation (rather than decreasing mRNA levels).
(From Darling TN. Molecular biology. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Philadelphia: Elsevier; 2018:66–80.)
Translational repression
37
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2
Dermatopharmacology
Alexander Maley and Ali Alikhan
CONTENTS LIST
2.1 ANTIHISTAMINES
2.2 RETINOIDS
2.3 CORTICOSTEROIDS
2.4 IMMUNOMODULATORY AGENTS
2.5 ONCOLOGIC AGENTS IN DERMATOLOGY
2.6 ANTIMICROBIAL AGENTS
2.7 PHOTOTHERAPY
2.8 MISCELLANEOUS AGENTS
2.9 DRUG INTERACTIONS AND THE CYTOCHROME P-450 SYSTEM
2.10 DRUG REACTIONS
2.1 ANTIHISTAMINES
Mechanism o action
Histamine is released by mast cells and is a mediator o
inammation when bound to its receptor
The primary unction o histamine is to stimulate local blood
vessels and nerves, producing vasodilatation and pruritus
■
H1 receptors are ound in the skin
■
H1 and H2 antihistamines are inverse agonists
(downregulate constitutively activated state o receptor)
or antagonists at histamine receptors
Important acts
Treatment o choice or mast cell disease, urticaria, and
angioedema
2014 atopic dermatitis guidelines do not recommend use
in atopic dermatitis outside o short-term use or sleep loss
First-generation H1 antihistamines
Adverse eects (AEs): sedation, impaired cognitive unction
(rom lipophilicity; cross blood-brain barrier, risk actor or
dementia), and anticholinergic eects (dry mouth,
constipation, dysuria, tachycardia, and blurred vision)
Diphenhydramine: topical ormulation → limited efcacy,
can cause contact dermatitis; sae in pregnancy
Cyproheptadine: intereres with hypothalamic unction →
may ↑ appetite and retard growth in children
Promethazine: used or allergies and urticaria, but may
cause respiratory depression (do not use in patients
, 2 years), tissue damage, extrapyramidal symptoms, and
neuroleptic malignant syndrome
Chlorpheniramine: historically sae in pregnancy
Hydroxyzine: strong afnity or muscarinic receptors, high
risk in patients aged . 65 years
Second-generation H1 antihistamines
Less sedating (because o ↓ ability to cross blood-brain
barrier) and lack anticholinergic eects
More selective or histamine receptors over muscarinic
receptors
2018 urticaria guidelines recommend over frst-generation
antihistamines or the treatment o urticaria
Recommended treatment in pregnancy and lactation
Fexoenadine: active metabolite o the prodrug terenadine
(which was withdrawn because o Q-T prolongation and
torsades de pointes); not metabolized by the liver and
excreted unchanged
Loratadine: ↓ dose in patients with hepatic or renal
impairment
Cetirizine: carboxylic acid metabolite o hydroxyzine;
both can cause systemic contact dermatitis due to
ethylenediamine; .10% get drowsiness (most sedating o
second-generation antihistamines); ↓ dose in patients
with hepatic or renal impairment
Levocetirizine: active metabolite and R-enantiomer o
cetirizine; suppresses histamine wheal better than
desloratidine and exoenadine
Desloratadine: active metabolite o loratadine, more
potent than loratadine in suppressing histamine wheal
39
CHAPTER 2 Dermatopharmacology
Other antihistamines
Doxepin: tricyclic antidepressant (TCA) with H
antihistamine activity; eective in urticaria and psychiatric
patients with neurotic excoriations; available orally and
topically (5% cream—can cause allergic contact
dermatitis, and sedation via absorption)
■
Much higher afnity or histamine receptors than most
antihistamines
■
Therapeutic eect longer lasting than diphenhydramine
and hydroxyzine because o long hal-lie (thus QHS
dosing)
■
Sedation is most common AE; others include
anticholinergic and orthostatic hypotension
■
Do not give with other antidepressants, or in severe
heart disease (risk o heart block)
■
Can ↓ seizure threshold
■
Can induce manic episodes in patients with manicdepressive disorder; black box warning or suicidality
(since it is an antidepressant)
and H
1
2.2 RETINOIDS (TABLES 2.1 AND 2.2)
Introduction
Retinoids are derived rom vitamin A
Three interconvertible orms: retinol (alcohol), retinal
(aldehyde), and retinoic acid (acid)
■
Retinoic acid is the active metabolite
Stored in the liver as retinol
Retinol is transported in plasma by binding to a complex
2
o retinol-binding protein and transthyretin
Mechanism
Binds cytosolic retinoid-binding protein → transported to
the nucleus → binds intracellular nuclear receptors
Binds to two amilies o nuclear receptors: retinoic acid
receptors (RARs) and retinoid X receptors (RXRs)
■
Each receptor amily contains three isotypes (a, b, and g)
■
RARs are homodimers, whereas RXRs can orm
heterodimers with other nuclear receptors: vitamin D,
thyroid hormone, and peroxisome prolieratoractivated receptors
■
The major receptors in keratinocytes are RXR-a and
RAR-g (most abundant in skin)
Photoaging → ↓ RXR-a and RAR-g
Binding to RAR/RXR aects various genes and transcription
actors that are involved in many unctions (cellular
prolieration, dierentiation, embryonic development,
cellular cohesiveness, and inammatory eects)
■
Inhibits AP1 and NF-IL-6, which are important in
prolieration and inammatory responses
■
Inhibits toll-like receptor 2, which is an activator o
inammatory cytokine responses
■
↓ Tumorigenesis and induces apoptosis
■
Antikeratinization (downregulates K6 and K16)
■
↑ Stratum corneum thickness, epidermal hyperplasia,
correction o atypia, dispersion o melanin granules,
Table 2.1 Topical Retinoids
Retinoid Generation
Tretinoin
(all-trans-RA)
Alitretinoin
(9-cis-RA)
Adapalene Third (poly
Tazarotene Third
Bexarotene Third Trace amounts 20 weeks All RXR CTCL patch/plaque
Triarotene Fourth Not measured, no
Retinol Precursor o
Retinaldehyde Precursor o
CTCL, Cutaneous T-cell lymphoma; RAR, retinoic acid receptor; RXR, retinoic X receptor; UV, ultraviolet.
First
(nonaromatic)
First Not measurable 4–8 weeks All RAR and
aromatic)
retinoic acid
retinoic acid
Systemic Absorption
(% Dose)
1%–2% in normal skin 8–12 weeks All RAR Acne, ine lines
Trace amounts 8–12 weeks
,5% in normal skin
changes in lab results
Timing o
Improvement
8–12 weeks
8–12 weeks,
signiicant
reduction seen
by 2 weeks
8–12 weeks Cosmeceutical product,
8–12 weeks Cosmeceutical product,
Nuclear
Receptor
Proile
RXR
RAR-b/g . a
RAR-b/g . a
RAR-g –
selective
Uses/Treatment
Indications Miscellaneous
and wrinkles,
hyperpigmentation
Kaposi sarcoma “AL(L) itretinoin binds
Acne, ine lines
and wrinkles,
hyperpigmentation
Acne, ine lines
and wrinkles,
hyperpigmentation and
plaque psoriasis
stage
Acne
photoaging, and
hyperpigmentation
photoaging, and
hyperpigmentation
Inactivated by UV →
apply at night
Oxidized by benzoyl
peroxide
ALL orms (RARs and
RXR) o receptors”
Light stable
Teratogenic
“beXarotene 5 RXR”
Teratogenic
Selectivity or g receptor
results in less irritation
40
2.2 Retinoids
Table 2.2 Systemic Retinoids
Retinoid Generation Hal-Lie Metabolism Excretion
Tretinoin (ATRA
or all-trans-RA)
Isotretinoin
(13-cis-RA)
Etretinate Second (mono-
Acitretin Second 2 days Hepatic, re-
Bexarotene Third
a
Other o-label uses include: disorders o keratinization (ichthyosis, pityriasis rubra pilaris, keratoderma, acantholytic disorders), chemoprophylaxis o
premalignant and malignant skin cancers (typically acitretin; nevoid basal cell carcinoma syndrome, xeroderma pigmentosum, and transplant patients).
ASDS, American Society or Dermatologic Surgery; CTCL, cutaneous T-cell lymphoma; PUVA, psoralen plus ultraviolet light A; RAR, retinoic acid receptor; RXR,
retinoic X receptor; TG, triglyceride.
First
(nonaromatic)
First 20 hours Hepatic,
aromatic)
(polyaromatic)
1 hour Hepatic Bile, urine All RAR Acute promyelocytic
metabolizes
to tretinoin
120 days Hepatic,
metabolizes
to acitretin
esteriication
to etretinate
by alcohol
7–9 hours Hepatic Hepato-biliary All RXR CTCL resistant to at
Bile, urine None No longer available 50 times more
Bile, urine None Psoriasis (pustular,
Nuclear Receptor
Proile Uses/Treatment
leukemia
ment-resistant moderate acne
Usual dose: 0.5–2
mg/kg/day
Goal cumulative dose:
120–220 mg/kg or
severe acne
Take with a atty meal
(lipophilic), ormulation o isotretinoin
with lidose OK to
take on empty
stomach
Women must have
2 negative
pregnancy tests
prior to initiating;
requires 2 orms o
contraception or
1 month beore,
during and 1 month
ater cessation o
therapy (abstinence
is an alternative)
erythrodermic,
severe and
recalcitrant
plaque)
Can be combined with
PUVA (Re-PUVA);
acitretin is given
10–14 days prior to
starting PUVA,
which accelerates
the response
Usual dose: 25–50
mg/day
least one systemic
therapy
Usual starting dose is
75 mg/day up to
300 mg/day
Response to treat-
ment takes up to 6
months
a
Miscellaneous
Treats acute
Only retinoid to
Avoid with tetra-
All patients must
Stop beore LASIK
ASDS guidelines
Must avoid preg-
Must avoid con-
Central hypothy-
Avoid gembrozil
“beXarotene 5 RXR”
promyelocytic
leukemia (APML)
aect sebum
production so
Cutibacterium
acnes unable to
thrive
cyclines (↑ risk
o pseudotumor
cerebri)
enroll in iPLEDGE
or pregnancy
prevention
→ risk o dry eye
state do not need
to delay supercial
chemical peel,
supercial
dermabrasion,
non-ablative
laser. Fully ablative
laser should be
avoided or
6 months
lipophilic than
acitretin → long
elimination
hal-lie
nancy 3 years
ater therapy
current alcohol
use (alcohol →
conversion to
etretinate → increased hal-lie
and increased teratogenicity)
roidism, leukopenia, ↑ TG
(worsens hyperTG)
41
CHAPTER 2 Dermatopharmacology
↓ melanosome transer to keratinocytes, ↑ dermal
collagen I, ↑ papillary dermal elastic fbers,
↑ hyaluronic acid, ↓ matrix metalloproteinases,
and ↓ angiogenesis
■
Inhibits ornithine decarboxylase
■
↑ TH1 cytokines and ↓ TH2 cytokines (helpul in
cutaneous T-cell lymphoma [CTCL])
Adverse eects o retinoids
Mucocutaneous
Topical retinoids: dermatitis, exoliation, and
photosensitivity
Systemic retinoids: cheilitis (#1 AE), thirst, dry nasal
mucosa, epistaxis, xerosis, xerophthalmia, palmoplantar
peeling, photosensitivity, exacerbation o eczema,
Staphylococcus aureus colonization in isotretinoin patients
telogen euvium, hair kinking, nail ragility/paronychia,
pyogenic granulomas, eruptive xanthomas, delayed
wound healing/keloid scar ormation, and sticky
sensation (palms and soles)
Systemic
Myalgias, arthralgias, anorexia, nausea, diarrhea,
abdominal pain, headache, pseudotumor cerebri (i
used in conjunction w/ tetracyclines), atigue, reduced
night vision, hepatitis, pancreatitis secondary to
hypertriglyceridemia, rarely bone toxicity (diuse
idiopathic skeletal hyperostosis; more common with
acitretin), calcifcation o tendons and ligaments, and
premature epiphyseal closure
Meta-analyses have reuted the development o depression
and inammatory bowel disease
Hyperlipidemia/hypertriglyceridemia: most common
laboratory abnormality; highest risk w/ bexarotene;
discontinue i asting triglycerides . 800 mg/dL because
o a pancreatitis risk
Elevated liver unction tests: usually transient; more
requent with acitretin than with isotretinoin or bexarotene;
consider discontinuation i .3X upper limit o normal
Central hypothyroidism (↓ TSH and T4): occurs in 80%
on bexarotene; start low-dose levothyroxine in all patients
Leukopenia (neutropenia) and agranulocytosis: most
common with bexarotene
Note: the antiretroviral drug indinavir has retinoid-
like AEs
Teratogenicity
50%–60% o isotretinoin-exposed pregnancies result in
“healthy-appearing” births (lack obvious retinoid
embryopathy)
■
However, ↓ mental unction becomes apparent in
majority o these children over time: 30% have gross
intellectual disability and 60% have mild-moderate
mental defcits
Most common AEs in pregnant patients exposed to
isotretinoin:
■
Spontaneous abortion (20%)
■
Retinoid embryopathy (18%–28%): cranioacial,
cardiac, CNS, and thymic abnormalities
Specifc eatures o retinoid embryopathy:
Cranioacial: microtia, clet palate, mircophthalmia,
hypertelorism, dysmorphic acies, and ear abnormalities
CNS: microcephaly, hydrocephalus, CNVII palsy, and
cortical and cerebellar deects
CV: cardiac septal deects, tetralogy o Fallot, transposition
o great vessels, and aortic arch hypoplasia
Thymic: thymic aplasia/ectopia
Note: no risk o retinoid embryopathy reported in male
partners taking retinoids.
Contraindications
Absolute: pregnancy, women contemplating pregnancy,
noncompliance with contraception, breasteeding, hypersensitivity to parabens (some capsules may contain parabens)
Relative: leukopenia, moderate-to-severe hypercholesterolemia
or hypertriglyceridemia, signifcant hepatic or renal
dysunction, and hypothyroidism (bexarotene)
Interactions
Oral retinoids are lipophilic → atty meals
↑ bioavailability
Avoid vitamin A supplements (hypervitaminosis A)
Methotrexate (MTX) → increased liver toxicity
Alcohol 1 acitretin → conversion o acitretin to etretinate
(longer hal-lie → increased teratogenicity)
Isotretinoin 1 tetracyclines → pseudotumor cerebri
Bexarotene 1 gemfbrozil → bexarotene is metabolized
by cytochrome P-450 3A4; avoid with gemfbrozil as it
inhibits 3A4 → ↑ plasma levels o bexarotene → severe
hypertriglyceridemia
■
Treatment o ↑ LDL: statin (may use any except
simvastatin, because it interacts with 3A4)
■
Treatment o ↑ triglycerides: enofbrate and/or omega 3
2.3 CORTICOSTEROIDS
Pharmacology key points (Table 2.3)
Basic structure 5 three hexane rings and one pentane
ring—modifcations to this structure result in various
corticosteroids (CS; e.g., addition o 1,2 double bond to
hydrocortisone → prednisone)
CS used in dermatology achieve their desired eects via
glucocorticoid activity; mineralocorticoid (MC) eects
are never desirable (sodium and water retention,
hypertension [HTN])
■
Short-acting (hydrocortisone and cortisone):
↓ glucocorticoid, ↑ MC activity
■
Intermediate-acting (prednisone, prednisolone,
methylprednisolone, and triamcinolone):
↑ glucocorticoid and ↓ MC activity
■
Long-acting (dexamethasone and betamethasone):
↑↑ glucocorticoid, no MC activity
Glucocorticoid receptor binds to CS in the cytoplasm →
translocates to nucleus → binds nuclear DNA to act as
transcription actor → altered gene regulation/
transcription
42
2.3 Corticosteroids
Table 2.3 Pharmacology Key Concepts: Systemic Corticosteroids
Glucocorticoid
Corticosteroid Equivalent Dose (mg)
Short-acting
Cortisone 25 0.8
Cortisol (hydrocortisone) 20 1
Intermediate-acting
Prednisone 5 4
Prednisolone 5 4
Methylprednisolone 4 5 0 180 24–36
Triamcinolone 4 5 0 78–188 24–36
Long-acting
Dexamethasone 0.75 20–30 0 100–300 36–54
Betamethasone 0.6–0.75 20–30 0 100–300 36–54
a
Glucocorticoid potency is expressed in a relative scale without specifc units o measure; this relative potency number is inversely related to the equivalent dose
in the frst column.
From Wolverton S. Comprehensive Dermatologic Drug Therapy . 3rd ed. Philadelphia: Elsevier; 2012.
Potency
a
Mineralocorticoid
Potency
2 1
2 1
1 1
1 1
Plasma Hal-Lie
(minutes)
30–90 8–12
60–120 8–12
60 24–36
115–212 24–36
Biologic Hal-Lie
(hours)
Cortisol-binding globulin (CBG) is main carrier protein—
steroid that is bound to CBG is inactive and unbound
steroid (ree raction) is active
■
↑ CBG: estrogen therapy, pregnancy, and
hyperthyroidism → ↓ CS ree raction
■
↓ CBG: hypothyroidism, liver disease, renal disease,
and obesity → ↑ CS ree raction
11b-hydroxysteroid dehydrogenase in liver converts
steroids to active orms:
■
Cortisone (inactive orm) → cortisol (aka
hydrocortisone, active orm)
■
Prednisone (inactive orm) → prednisolone (active
orm)
■
Liver disease can impair conversion → preerable to
give active orms o steroids in this setting (e.g.,
prednisolone instead o prednisone)
Mechanism o action (MoA) via immunosuppressive and
anti-inammatory eects, primarily via cytokine
alterations (e.g., ↓ proinammatory cytokines and ↑ antiinammatory cytokines)
■
Decreased: NF-B, AP-1, phospholipase A2,
eicosanoids (e.g., leukotrienes, prostaglandins, 12HETE, and 15-HETE), COX-2, activity o all types o
WBCs, fbroblast activity, and prostaglandin production
■
Increased: IL-10 (major downregulator o cell-mediated
immunity), anti-inammatory proteins (e.g.,
vasocortin, lipocortins, and vasoregulin), and
↑ apoptosis o lymphocytes and eosinophils
■
Major eects on cellular immunity (. humoral
immunity) and cell trafcking
Physiologic CS 5 5 to 7.5 mg/day o prednisone
■
Serum cortisol peaks between 6 and 8 a.m.
Adverse eects (systemic)
Hypothalamic-pituitary-adrenal (HPA) axis suppression (Box 2.1)
Resulting rom systemic steroids . topical CS
Hypothalamus releases corticotropin-releasing actor
(CRH) → anterior pituitary releases adrenocorticotropic
hormone (ACTH) → adrenal glands release cortisol
HPA axis (CRH → ACTH → cortisol) is suppressed by use
o exogenous CS
■
Hypothalamus: frst to be suppressed, but quickest to
recover
■
Adrenals: last to be suppressed, but slowest to recover
MC axis (renin-angiotensin-aldosterone) is NOT
suppressed by exogenous CS used in dermatology → true
adrenal (Addisonian) crisis does not occur because o the
preserved MC axis unction
Exogenous adrenal insufciency (HPA axis suppression)
typically seen in patients taking pharmacologic CS doses
or $3 to 4 weeks
Risk actors:
■
Abrupt cessation o CS (taper i CS course is
. 4 weeks)
■
Major stressor (surgery, trauma, or illness)
■
Divided dosing (BID or TID)
■
Daily dose given at any time other than the morning
Alternate-day (QOD) dosing → ↓ risk o nearly all major
complications
■
↓ Risk o: HPA axis suppression, growth suppression,
HTN, opportunistic inections, and electrolyte
disturbances
■
Does not lower risk o: cataracts or osteoporosis
Exogenous adrenal insufciency most commonly presents
as steroid withdrawal syndrome: arthralgias, myalgias,
mood changes, headache, atigue, and anorexia/nausea/
vomiting; no change in serum cortisol level, but rather
↓ available intracellular CS
Box 2.1 Layman’s Explanation o Exogenous Adrenal Insuciency
I you keep giving a person systemic steroids with glucocorticoid (cortisollike) eects, their adrenal glands become “lazy” and stop making
endogenous cortisol → over time, the adrenals become shrunken/atrophic,
and can no longer produce adequate cortisol; immediately upon cessation
o systemic steroid administration → “exogenous adrenal insuciency” as a
result o insucient cortisol → may appear to be steroid withdrawal
syndrome (most common), or very rarely, adrenal (Addisoniana) crisis.
a
O note, the mineralocorticoid axis (renin-angiotensin-aldosterone) is al-
most NEVER suppressed in “exogenous adrenal insufciency” → almost
never get true adrenal (Addisonian) crisis with hypotension, coma.
43
CHAPTER 2 Dermatopharmacology
Glucocorticoid eects
Hyperglycemia and increased appetite/weight gain
Mineralocorticoid eects (tend to occur with
CS with high MC eect)
As a result o “aldosterone-like” activity o some CS
HTN, congestive heart ailure (CHF), weight gain, and
hypokalemia
Lipid eects
Hypertriglyceridemia (may result in acute pancreatitis),
cushingoid changes, menstrual irregularity, and lipodystrophy
(moon ace, bualo hump, and central obesity)
Pediatric eects
Growth impairment (as a result o ↓ growth hormone and
IGF-1 production)
↓ risk with QOD dosing
Musculoskeletal/vascular eects
Osteoporosis: QOD dosing does NOT ↓ risk; consider
calcium 1 vitamin D and/or bisphosphonates, teriparatide,
nasal calcitonin; greatest reduction in bone mass occurs
in frst 6 months; ↑ racture risk in postmenopausal
women; greatest absolute loss o bone mass occurs in
young men (they have highest baseline bone mass)
Osteonecrosis: usually at least 2- to 3-month courses;
proximal emur most common
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Imaging test o choice: MRI
Hypocalcemia
Venous thromboembolism
Gastrointestinal eects
Bowel peroration, peptic ulcer disease (mainly i total
dose $ 1 g, H2 antagonists or proton pump inhibitors can
help), atty liver changes, esophageal reux, and nausea/
vomiting
Ocular eects
Cataracts (risk does NOT change with QOD dosing),
glaucoma, inections, and reraction changes
Cutaneous eects
↓ wound healing, striae, atrophy, telangiectasias, steroid
acne, purpura, inections (staphylococcal, herpes virus),
telogen euvium, hirsutism, generalized pustular
psoriasis (upon drug withdrawal), perioral dermatitis,
contact dermatitis, and hypopigmentation
Contraindications
Systemic ungal inections, herpes simplex keratitis, and
steroid allergy
Pregnancy
Likely sae or short courses—high dose may result in
intrauterine growth retardation and inhibition o
endogenous corticosteroid production
Clinical use
Inammatory dermatoses (atopic and allergic contact
dermatitis, urticaria, connective tissue disorders,
vasculitides, neutrophilic dermatoses, autoimmune
blistering disease, papulosquamous dermatoses, drug
reactions): commonly dosed at 0.5 to 2 mg/kg/day
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A steroid-sparing immunosuppressive drug is
oten used concurrently or chronic inammatory
disease
Toxicodendron dermatitis: short steroid taper →
↑ likelihood o rebound are; best option is a 3-week
tapering course starting at about 1 mg/kg daily
Note: oral CS ↓ acute pain in herpes zoster, but likely do
not prevent postherpetic neuralgia
Longer duration o treatment 5 ↑ AE risk
Divided dose regimens are more eective, but have a
higher risk o AEs than single-dose regimens (best taken
in AM to simulate body’s diurnal variation o cortisol
production)
QOD dosing: the anti-inammatory eects o CS last
longer than the HPA axis suppressive eects → QOD
dosing helps maintain control o disease activity ater
course with daily CS
Psychiatric changes
Psychosis, hypomania, insomnia, agitation, and
depression
Neurologic eects
Pseudotumor cerebri, seizures, epidural lipomatosis, and
peripheral neuropathy
Opportunistic inections
Tuberculosis (TB) reactivation, deep ungi, prolonged
herpes virus inections, and Pneumocystis jiroveci
pneumonia
↓ risk with QOD dosing
Muscular eects
Myopathy (proximal lower extremity weakness) and
muscular atrophy
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Intramuscular CS
Unique AEs: cold abscesses, subcutaneous at atrophy,
crystal deposition, menstrual irregularities, and
purpura
Main advantages (vs. oral CS): compliance, can be given
in setting o nausea/vomiting
Main disadvantages (vs. oral CS): ↑ HPA axis
suppression because levels are constant throughout the
day (↑ requency o intramuscular [IM] injections →
↑ risk o HPA axis suppression), and less ability to
precisely taper
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Per Wolverton, do not use long-acting IM CS (such as
triamcinolone) .3 to 4 times/year
Pulse IV CS
Generally 0.5 to 1 g o methylprednisolone intravenously
(IV) over $1 hour 3 5 consecutive days