2 Dermatopharmacology Flashcards
1
Q
Histamine levels are elevated in the skin of pts with?
A
Chronic urticaria
2
Q
Itching is largely mediated by which type of histamine receptors?
A
H1 receptors
3
Q
MoA of H1, H2 antihistamines
A
inverse agonists
(downregulate constitutively activated state of receptor)
or
antagonists at histamine receptors
4
Q
Location of H1 receptors
A
Periphery of the body
Adrenal medulla
Vascular endothelium
Heart
CNS
5
Q
H1 receptor functions (5)
A
Ileum contraction
Modulate circadian cycle
Itching
Systemic vasodilation
Bronchoconstriction
6
Q
Name some H1 receptor antagonists
A
Diphenhydramine
Loratadine
Cetirizine
Fexofenadine
Clemastine
7
Q
H1 receptor definition
A
Histamine receptors that couple to Cq/11 stimulating phospholipase C
8
Q
H2 receptor definition
A
Histamine receptors that interact with Gs to activate adenylyl cyclase
9
Q
Location of H2 receptors
A
CNS
Parietal cells of the stomach
10
Q
H2 receptor functions
A
Speed up sinus rhythm
Stimulation of gastric acid secretion
Smooth muscle relaxation
Inhibit antibody synthesis
T-cell proliferation, cytokine production
11
Q
Name some H2 antagonists
A
Ranitidine
Cimetidine
Famotidine
Nizatidine
12
Q
H1 antihistamines are primarily used in dermatology in?
A
Urticaria
and some cases of eczema
13
Q
H1 antagonists can be used as monotherapy in urticaria and eczema
T/F?
A
False
14
Q
H2 antihistamines can be added for chronic urticaria, but evidence is poor
T/F?
A
True
15
Q
Name 2 H1 antagonists that are safe to use in pregnancy and lactation
A
Diphenhydramine
Chlorpheniramine
(both of them have long safety record)
16
Q
Antihistamines are primarily used for?
A
Urticaria
Angioedema
(not great option for atopic dermatitis)
17
Q
Which type of antihistamines is preferred for nocturnal pruritus?
A
first-generation H1 antihistamines
18
Q
Adverse effects of
first-generation H1 antihistamines
A
sedation
impaired cognitive function
(from lipophilicity; cross blood-brain barrier)
anticholinergic effects
(dry mouth, constipation,dysuria and blurred vision)
19
Q
Examples of first-generation H1 antihistamines
A
Diphenhydramine
Cyproheptadine
Promethazine
Chlorpheniramine
Hydroxyzine
20
Q
In which pregnancy drug category belong diphenhydramine and chlorpheniramine?
A
Pregnancy category B
“Adverse effects on animal studies only
Adequate human studies lacking or not shown similar results. Can be used in pregnancy”
21
Q
Specific side effect of cyproheptadine?
A
interferes with hypothalamic function →
may ↑appetite and retard growth in children
22
Q
Difference btw 2nd and 1st gen antihistamines
A
2nd gen:
- Less sedating (↓ability to cross blood-brain barrier)
- lack anticholinergic effects
- Appear to be relatively equivalent for dermatologic indications (e.g., chronic urticaria)
23
Q
Examples of 2nd gen antihistamines
A
Fexofenadine
Loratadine
Cetirizine
Desloratadine
Levocetirizine
24
Q
Characteristics of Fexofenadine
A
- active metabolite of the prodrug terfenadine (which was withdrawn because of Q-T elongation and torsades de pointes)
- not metabolized by the liver and excreted unchanged
25
Name 2 second gen antihistamines that can be used in pregnancy
Loratadine
Cetirizine
↓dose in patients with hepatic or renal impairment
26
Name the active metabolites of:
1. Loratadine
2. Cetirizine
1. Desloratadine: 5× more potent than loratadine in suppressing histamine wheal
2. Levocetirizine: active metabolite and R-enantiomer of cetirizine
27
TCA with H1 and H2 antihistamine activity
Doxepin
available both orally and topically
28
Indications of doxepin?
effective in urticaria and depressed patients with neurotic excoriations
29
SE of topical 5% doxepin cream
can cause allergic contact dermatitis and drowsiness
30
Benefits of doxepin vs rest of antihistamines
* Much higher affinity for histamine receptors than
most antihistamines
* Therapeutic effect longer lasting than
diphenhydramine and hydroxyzine because of long
half-life (thus QHS dosing)
31
SE of doxepin?
* Sedation (MC SE)
* anticholinergic SEs
* orthostatic hypotension
32
Warnings of doxepin?
* Do not give with other antidepressants, or with severe
heart disease (risk of heart block)
* Can ↓seizure threshold
* Can induce manic episodes in patients with manic-
depressive disorder
* Black box warning for suicidality
33
Definition of retinoids
Vitamin A and related natural and synthetic compounds
34
Name the 3 interconvertible forms of retinoids
* retinol (alcohol)
* retinal (aldehyde)
* retinoic acid (acid)
35
Other characteristics of retinoids?
* Acquired through diet (dairy, fish, meat, eggs, leafy greens, and orange/yellow vegetables)
* Carotenoids (beta-carotene) are precursors of vitamin A
* Stored in the liver as retinol
* Retinol is transported in plasma by binding to a complex of retinol binding protein and transthyretin
36
MoA of retinoids
* Binds cytosolic retinoid binding protein → transported to the nucleus → binds intracellular nuclear receptors
* Binds to two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs)
Each receptor family contains 3 isotypes (α, β,
and γ)
37
Name the major intercellular retinoid nuclear receptors in keratinocytes
RXR-α
and
RAR-γ (most abundant in skin)
38
What is the impact of photoaging in retinoid receptors?
↓RXR-α and RAR-γ
39
MoA of topical retinoids
↑stratum corneum thickness,
epidermal hyperplasia,
correction of atypia,
dispersion of melanin granules,
↑dermal collagen I,
↑papillary dermal elastic fibers,
↑hyaluronic acid,
↓matrix metalloproteinases,
↓angiogenesis
40
What is the impact of retinoids binding to RAR/RXR?
* Inhibits AP1 and NF-IL-6, which are important in proliferation and inflammatory responses
* Inhibits TLR2, which is important in inflammation
* ↓tumorigenesis and induces apoptosis
* Antikeratinization (downregulates K6 and K16)
* Inhibits ornithine decarboxylase
* ↑TH1 cytokines and ↓TH2 cytokines (helpful in CTCL)
41
What is the earliest and most common SE of retinoids?
Cheilitis
42
Name a few mucocutaneous SEs of retinoids
Thirst
dry nasal mucosa
epistaxis
xerosis
xerophthalmia
palmoplantar peeling
photosensitivity
exacerbation of eczema
nail fragility
sticky sensation (palms and soles)
43
What type of alopecia can be triggered by retinoids?
telogen effluvium
44
What is the result of dryness of the nasal mucosa in pts on retinoid treatment?
Staphylococcus aureus colonization of the nasal mucosa (75%–90%)
45
Pt with nodulocystic acne, treated with topical tazarotene, presents with a dome-shaped well demarcated erythematous lesion on the left cheek.
Dx?
Pyogenic granuloma-like lesions
(commonly seen in pts on either oral or topical retinoid tx)
46
Name some systemic SEs of retinoids?
Myalgias
arthralgias
anorexia
nausea
diarrhea
abdominal pain
IBD (controversial)
headache
fatigue
reduced night vision
questionable depression/suicidal ideation
hepatitis
pancreatitis secondary to hypertriglyceridemia
calcification of tendons and ligaments
premature epiphyseal closure
47
MC lab abnormality of pts on retinoids?
Highest risk with?
Hyperlipidemia/hypertriglyceridemia
bexarotene
48
When should you discontinue tx with retinoids and why?
* fasting TGs \>800 mg/dL ( ^pancreatitis risk)
* LFTs greater than 3× the upper limit of normal
49
Pt on retinoid therapy presents with ^LFTs after 4 weeks of tx.
BNS?
Continue tx with the same dose
^ LFTs are usually transient within 2 to 8 weeks of starting treatment, return to normal after another 2 to 4 weeks of treatment
50
^LFTs are more frequent with?
acitretin
(lower risk with isotretinoin or bexarotene)
51
Current recommendations are to start low-dose
levothyroxine in all patients on retinoids
T/F?
True
80% of pts on bexarotene present with reversible central hypothyroidism (Decreased TSH and T4)
52
Hematologic SEs of bexarotene?
Leukopenia (neutropenia) and agranulocytosis
53
Pt on isotretinoin tx gives birth to a normal appearing baby
How would you interpret this phenomenon?
50%–60% of isotretinoin-exposed pregnancies result in “healthy-appearing” births (lack obvious retinoid embryopathy)
↓mental function becomes apparent in
majority of these children over time: 30% have gross mental retardation and 60% have mild-moderate mental deficits
54
MC adverse results in pregnant patients exposed to isotretinoin?
* Spontaneous abortion (20%)
* Retinoid embryopathy (18%–28%): craniofacial,
cardiac, CNS, and thymic abnormalities are most
common
55
Features of retinoid embryopathy
* Craniofacial: microtia, cleft palate, mircophthalmia, hypertelorism, dysmorphic facies, and ear abnormalities
* CNS: microcephaly, hydrocephalus, CN7 palsy, and cortical and cerebellar defects
* CV: cardiac septal defects, tetralogy of Fallot, transposition of great vessels, and aortic arch hypoplasia
* Thymic: thymic aplasia/ectopia
* No risk of retinoid embryopathy reported in male
partners taking retinoids; however, iPledge requires male registration because pregnancies have been reported where women have “borrowed” their male partner’s medication
56
Absolute CIs to retinoid therapy
pregnancy
women contemplating pregnancy
noncompliance with contraception
breastfeeding
hypersensitivity to parabens
(some capsules may contain parabens)
57
Relative CIs to retinoid tx
leukopenia
moderate/severe hypercholesterolemia or hypertriglyceridemia
significant hepatic or renal dysfunction
hypothyroidism (bexarotene)
58
Combination of Isotretinoin + tetracyclines can lead to?
Pseudotumor cerebri
59
Combination of alcohol + acitretin can lead to?
conversion of acitretin to etretinate
hepatotoxicity
60
Oral retinoids are lipophilic → fatty meals ↑bioavailability
T/F?
True
61
Combination of Bexarotene + gemfibrozil can lead to?
severe hypertriglyceridemia
bexarotene is metabolized by cytochrome P450 3A4; avoid with gemfibrozil as it inhibits 3A4 → ↑plasma levels of bexarotene
62
Tx of ^LDL in pts on retinoids can be implemented with any statin, except?
simvastatin
(interacts with CYP450 3A4)
63
Treatment of ↑TG in pts on retinoids?
fenofibrate and/or omega 3
64
Drugs to avoid while on retinoid tx?
* Vitamin A supplements ( risk of hypervitaminosis A)
* MTX (increased liver toxicity)
* Tetracyclines (^ risk of pseudotumor cerebri)
* Gemfibrozil (severe hypertriglyceridemia)
* Simvastatin ( \<\< \<\<)
65
Name some topical retinoids
Tretinoin (all-trans retinoid acid)
Alitretinoin (9-cis-RA)
Adapalene
Tazarotene
Bexarotene
Retinol
Retinaldehyde
66
Topical retinoids of pregnancy category X
Tazarotene
Bexarotene
67
Topical retinoid used in the Rx of Kaposi sarcoma?
Alitretinoin (9-cis-RA)
68
Features of topical tretinoin
1st gen (non aromatic)
1-2% of dose systemic absorption
Binds to all RAR nuclear receptors
Improvement in 8-12w
Apply at night (inactivated by UV)
Oxidized by benzoyl peroxide
69
Features of topical Alitretinoin (9-cis-RA)
1st gen
Not measurable systemic absorption
Binds to ALL forms of retinoid nuclear receptors(NRs)
(RAR & RXR)
ALLitretinoin binds to ALL forms of NRs
Improvement in 4-8weeks
70
Features of adapalene
3gen polyaromatic
Binds to RAR-β/γ \>α
LIGHT STABLE
Used for acne (hyperpigmentation, photoaging)
Improvement in 2-3mo
71
Features of tazarotene
3gen
Binds to RAR-β/γ\>α
\<5% of dose systemic absorption
Used for acne, plaque psoriasis
(hyperpigmentation,photoaging,disorders of keratinization, AKs)
category X
72
Features of topical bexarotene
3gen
Binds to all RXR nrs
(beXarotene binds to RXR)
Used for cutaneous T-cell lymphoma, hand dermatitis, psoriasis, alopecia areata, lymphomatoid papulosis(LyP)
Category X
73
Features of topical retinol & retinaldehyde
Precursor of RA
Used for photoaging, hyperpigmentation and as cosmeceutical product
Improvement in 2-3 mo
74
Table of topical retinoids
75
Name the most common systemic retinoids
* Tretinoin
* Isotretinoin
* Etretinate
* Acitretin
* Bexarotene
All of them pregnancy category X
76
Name the 1st generation systemic retinoids
and their IUPAC name
Tretinoin (ATRA or all-trans- RA)
Isotretinoin (13-cis- RA)
77
Features of tretinoin
* 1st gen systemic retinoid(nonaromatic)
* 1hr half-life
* Binds to al RAR
* Treats APML
78
Features of isotretinoin
* 1st gen systemic retinoid
* 20hr half-life
* Hepatic metabolism ( to tretinoin)
* Excretion via bile,urine
79
Uses and dose treatment of isotretinoin
* Severe acne & other follicular disorders
* Usual daily dose: 0,5-2mg/kg/d
* Goal cumulative dose: 120-150mg/kg for severe acne
80
SIs of isotretinoin in acne tx
* May flare in the first few weeks
* Lag period of 1-3 months before effect
* Continued healing after discontinuation
* 1/3 require 2nd course
81
Systemic SIs of isotretinoin
* Hyperostosis (long-term use)
* Pyogenic granulomas
* Excessive granulation response
* Telogen effluvium
* ^ Staph.aureus infections
82
Which type of drugs should not be administered while on isotretinoin tx?
Tetracyclines
^risk of pseudotumor cerebri
83
Special feature of isotretinoin
Only retinoid to affect sebum production
so P. acnes unable to thrive
84
Features of etretinate
* 2nd gen (monoaromatic)
* 120 days half-life
* Hepatic metabolism (to acitretin)
* Excreted via bile,urine
* 50 times more lipophilic than acitretin (persists very long)
85
Features of acitretin(Neotigason)
* 2nd gen
* 2 days half-life
* Hepatic metabolism (reesterification to etretinate by alcohol)
* Excreted via bile,urine
86
What is a strong recommendation for pts on acitretin?
Must avoid concurrent alcohol use
because alcohol converts acitretin-\>etretinate
--\> significantly prolonged effects
87
Uses of acitretin
Psoriasis (pustular, erythrodermic, severe & recalcitrant plaque)
88
What is RePUVA or ReUVB therapy?
acitretin is given 10–14 days prior to starting PUVA which
1. accelerates the response
2. decreases the carcinogenic risk of PUVA
Usual dose: 25–50 mg/day
89
Features of bexarotene(Targretin)
* The only 3rd gen (poly-aromatic)
* 7-9hr half-life
* Hepatic metabolism
* Excreted via hepatobiliary sysem
* Binds to al RXR
90
Uses of bexarotene
* CTCL resistant to at least one systemic therapy
* Usual starting dose: 75mg/day up to 300mg/day
* Response to tx takes up to 6 months
91
SIs of bexarotene?
Central hypothyroidism
↑↑TGs (severe)
Leukopenia
92
Special recommendations for pts on bexarotene
Avoid gemfibrozil (worsens hyper-TG)
"beXarotene - RXR"
93
Contraceptive therapy for female pts on systemic retinoid tx
* Isotretinoin,bexarotene:
1. 2 negative pregnancy tests prior to initiating
2. contraception for 1 month before, during, and 1 month after cessation of therapy)
* Same as above PLUS 3 year contraceptive therapy after cessation of tx
94
Other diseases where systemic retinoids may be used?
* Disorders of keratinization:
1. ichthyosis
2. pityriasis rubra pilaris
3. keratoderma
4. Darier's
* chemoprophylaxis of premalignant and malignant skin cancers:
1. nevoid basal cell carcinoma syndrome
2. xeroderma pigmentosum
3. transplant patients).
95
Basic pharmacological structure of corticosteroids(CS)
3 hexane rings and 1 pentane ring
modifications to this structure result in various CS (e.g.addition of 1,2 double bond to hydrocortisone → prednisone)
96
Exogenous corticosteroids are absorbed in?
Upper jejunum
(more than 50% of prednisone is absorbed)
97
CS in dermatology achieve their desired effects via?
Glucocorticoid activity
mineralocorticoid effects are never desirable (sodium and water retention, HTN) for dermatologic purposes
98
Short-acting (hydrocortisone and cortisone)
↓glucocorticoid, ↑mineralocorticoid activity
99
Intermediate-acting (prednisone, prednisolone, methylprednisolone, and triamcinolone)
↑glucocorticoid and ↓mineralocorticoid activity
100
Long-acting (dexamethasone and betamethasone)
↑↑glucocorticoid, no mineralocorticoid activity
101
Cortisol-binding globulin (CBG) is main carrier protein
steroid that is bound to CBG is inactive and unbound steroid (free fraction) is active
T or F?
True
102
Conditions that ↑ Cortisol-binding globulin (CBG)
↑CBG:
* estrogen therapy
* pregnancy →
* hyperthyroidism
↓CS free fraction
103
Conditions that ↓ Cortisol-binding globulin (CBG)
↓CBG:
* hypothyroidism
* liver disease →
* renal disease
* obesity
↑CS free fraction
104
Intracellular transport of CS
Glucocorticoid receptor (GCR) binds to CS in the cytoplasm
→ translocates to nucleus
→ binds nuclear DNA to act as transcription factor
→ altered gene regulation/transcription
105
Name the hepatic enzyme that converts CS from their inactive to active forms, as wells as some pairs of them
PS: Liver disease can impair conversion → preferable to
give active forms of steroids in this setting
(eg, prednisolone instead of prednisone)
11β-hydroxysteroid dehydrogenase
* Cortisone (inactive form) → cortisol
(aka hydrocortisone, active form)
* Prednisone (inactive form) → prednisolone (active
form)
106
MoA of CS?
Via immunosuppressive and antiinflammatory effects, primarily via cytokine alterations (e.g., ↓proinflammatory cytokines and ↑antiinflammatory cytokines
Major effects on cellular immunity (\> humoral immunity) and cell trafficking
107
Use of CS cause reduction in?
* NFκB, AP-1,
* phospholipase A2,
* eicosanoids (e.g., leukotrienes, prostaglandins, 12-HETE, and 15-HETE),
* COX-2,
* activity of all types of WBCs,
* fibroblast activity
* prostaglandin production
108
Use of CS cause increase in?
* IL-10 (major downregulator of cell- mediated immunity)
* antiinflammatory proteins (e.g., vasocortin, lipocortins, and vasoregulin)
* ↑apoptosis of lymphocytes and eosinophils
109
Distinction btw physiologic & pharmacological CS therapy
Physiologic CS therapy = 5 to 7.5 mg/day of prednisone
pharmacologic is anything higher
110
Pharmacology Key Concepts – Systemic Corticosteroids
111
Main adverse effects of systemic CS
HPA axis suppression
Hypertriglyceridemia
Lipodystrophy
Osteoporosis
Bowel perforation, PUD
Cataracts, glaucoma
Psychosis, hypomania
Pseudotumor cerebri, seizures
112
Features of CS-induced myopathy
Proximal lower extremity weakness
NORMAL LAB VALUES(MG & CK)!!!
113
Risk of HPA axis suppression with topical CS does it exist?
nearly nonexistent
except in setting of whole-body clobetasol application for autoimmune blistering diseases
114
Layman’s Explanation of Exogenous Adrenal Insufficiency
If you keep giving a person systemic steroids with glucocorticoid (cortisol-like) effects, 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 of systemic steroid administration → “exogenous adrenal insufficiency” as a result of insufficient cortisol → may appear to be steroid withdrawal syndrome (most common), or very rarely, adrenal (Addisonian\*) crisis.
115
Features of HPA axis suppression from CS
* Hypothalamus: first to be suppressed, but quickest to recover
* Adrenals: last to be suppressed, but slowest to recover
116
True Addisonian crisis w/ severe hypotension and coma is extremely uncommon in pts on CS therapy
True / False?
True
RAAS is NOT suppressed by exogenous CS used in dermatology
Mineralocorticoid axis is preserved
117
When is HPA axis suppression typically seen?
Pts taking pharmacologic CS doses for ≥3 to 4 weeks
118
Risk Factors of HPA axis suppression
* Abrupt cessation of CS (always taper if 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
119
Benefits of QOD (alternate) dosing in CS therapy?
↓risk of: HPA axis suppression, growth suppression,
HTN, opportunistic infections, and electrolyte
disturbances
120
QOD dosing in CS therapy reduces the risk of cataracts and osteoporosis
True/ False?
False
121
Exogenous adrenal insufficiency can present under 2 clinical forms
* Steroid withdrawal syndrome (SWS)
* Adrenal (Addisonian) crisis
122
Steroid withdrawal syndrome is ass/w arthralgias, muscle weakness, anorexia, fatigue and ↓cortisol levels
True/ False?
SWS presents with normal serum cortisol levels
but rather ↓available intracellular CS
123
Features of Addisonian crisis
p/w symptoms of SWS + hypotension, ↓↓↓cortisol levels
124
What SIs do CS with high mineralocorticoid activity cause?
HTN, CHF, weight gain, and hypokalemia
125
Considerations on using systemic CS in pediatric population?
Growth impairment (as a result of ↓growth hormone and IGF-1 production)
Can be eased with QOD dosing (↓risk)
126
Features of osteoporosis in CS tx
* consider calcium + vitamin D +/- bisphosphonates, teriparatide, nasal calcitonin
* greatest reduction in bone mass occurs in first 6 months
* ↑fracture risk in postmenopausal women
* greatest absolute loss of bone mass occurs in young men (they have highest baseline bone mass)
127
Bone SE of CS tx
* Osteoporosis
* Osteonecrosis (usually at least 2 to 3 month courses; proximal femur most common)
* Hypocalcemia
128
Name some opportunistic infections with ^ occurrence in CS tx?
* Tuberculosis reactivation
* deep fungi
* prolonged herpes virus infections
* Pneumocystis jiroveci pneumonia
129
Cutaneous SEs of CS tx
* ↓wound healing
* striae
* atrophy
* telangiectasias
* steroid acne
* purpura
* infections (staphylococcal, herpes virus)
* telogen effluvium
* hirsutism
* pustular psoriasis flare (upon drug withdrawal),
* perioral dermatitis, contact dermatitis
* hypopigmentation
130
CIs to systemic CS use
* Systemic fungal infections
* herpes simplex keratitis
* hypersensitivity reactions
131
Can systemic CS be used during pregnancy?
If so name two cutaneous diseases
Category C, but likely safe for short courses if needed
severe PUPPP or gestational pemphigoid
PUPPP = Pruritic urticarial papules and plaques of pregnancy
132
CS dose in pemphigus
start at 1 mg/kg daily in divided doses
^ up to 2 mg/kg daily (if needed) for 4 to 6 weeks,
consolidate dose to once a day & taper quickly to 40 mg daily, and slowly thereafter; a steroid-sparing agent should either be started at the get-go or
before tapering
133
CS in toxicodentron dermatitis tx
* DO not to stop oral CS too early because of the ↑likelihood of flare;
* best option is a 3 week tapering course starting at about 1 mg/kg daily
134
Effect of CS in herpes zoster tx
↓acute pain in herpes zoster, but likely do not prevent postherpetic neuralgia
135
Why do we prefer single dose regimens in CS tx over divided ones?
Divided dose regimens are more effective, but have a
higher risk of SEs than single dose regimens (best taken in AM to simulate body’s diurnal variation of cortisol production)
136
Benefits of QOD dosing in CS
* the antiinflammatory effects of CS last longer than the HPA axis suppressive effects
* QOD dosing helps maintain control of disease activity after course with daily CS
137
Adverse effects of IM CS?
* Cold abscesses (!!!)
* subcutaneous fat atrophy
* crystal deposition
* menstrual irregularities
* purpura
138
Pulse IV CS dose & SE
* Generally 0.5–1 g of methylprednisolone IV over ≥ 1 h × 5 consecutive days
* Indications: systemic vasculitis, SLE, pyoderma gangrenosum, and bullous pemphigoid
* Adverse effects: sudden cardiac death, atrial fibrillation, anaphylaxis, electrolyte shifts, seizures
139
Monitoring tests while on systemic CS tx
* Fasting glucose levels, BP (mild ↑ is ok), triglycerides
* weight
* height/weight for children
* DEXA scans (T score \< −2.5 = osteoporosis)
* MRI if pain in hip/ shoulder/knee (osteonecrosis)
* slit-lamp examination q6–12 months
* TB screening and CXR
140
Tests to evaluate adrenal insufficiency
■ AM cortisol: primary screening tool, \>10 mcg/dL = good basal adrenal function
■ 24 hour urine free cortisol: more accurate test for
basal adrenal function (advantage); main disadvantage
is patient compliance with 24 hour urine collection
■ ACTH stimulation: most commonly used provocative
test for adrenal function; check basal cortisol level → then inject ACTH → check cortisol levels at 30 and 60 minutes
141
Apremilast features
PDE-4 inhibitor
Used for psoriasis and PA
MC SEs: Diarrhea, nausea (resolve on
their own within 4 weeks usually)
LC SEs: Depression, weight loss
142
Advantage of Apremilast
No laboratory monitoring required
(Dose halved in patients with severe renal impairment)
143
Name 2 JAK inhibitors
Tofacitinib
Ruxolitinib
144
Features of Tofacitinib
JAK 1 and 3 inhibitor
• FDA approved for moderate to severe RA who have failed MTX
• Topical and oral have been tested in psoriasis; reports of
oral used in alopecia areata
• MC SEs: URI, mild headaches, and nausea
• May have ↓Hb and mean neutrophil count, but
usually normalize on treatment
• May have ↑LDL, HDL, CK, TGs, and LFTs
• Tuberculosis reactivation not reported
145
Features of Ruxolitinib
* JAK 1 and 2 inhibitor
* FDA approved for treatment of intermediate- or high-risk myelofibrosis
* Topical version tested in psoriasis; reports of oral used in alopecia areata
* Mainly local SEs
146
Uses of azathioprine
Organ transplantation
Severe RA
Atopic dermatitis
Chronic actinic dermatitis
Oral LP
Behçet disease
Cicatricial/ bullous pemphigoid
Pemphigus
Dermatomyositis
147
MoA of azathioprine
Inhibits purine metabolism and cell division
(particularly in fast-growing cells that do not have a salvage pathway, like lymphocytes)
148
How is HGPRT enzyme implicated in the MoA of AZA?
Converts AZA to its active metabolite 6TG (thioguanine)
that shares similarities with endogenous purines so it gets incorporated in the DNA,RNA
&
inhibitis purine metabolism & cell division
149
Immunological effects of AZA
Diminishes T-cell function and antibody production by B-cells
150
Name two enzymes that convert AZA to inactive metabolites
Xanthine oxidase
&
thiopurine methyltransferase
151
What kind of drugs should be avoided while on AZA tx?
Drugs that
* ↓ activity of TPMT (measured by allele activity)
* ↓ xanthine oxidase (allopurinol, febuxostat)
↑AZA levels
↑risk of life-threatening myelosuppression
152
Other drugs that increase risk of myelosuppression if they are used in concomitance with AZA
ACEIs
Sulfadiazine
Folate antagonists (TMP-SMX, MTX)
153
MC SEs of AZA
Nausea, diarrhea, vomiting
(present btw 1-10 days of tx)
Transaminase elevation
154
Usage of AZA for dermatologically dosed indications increases risk of cSCC and non-Hodgkin BCL
True / False?
False
Squamous cell carcinoma (SCC) and lymphoma (particularly non-Hodgkin’s B-cell lymphoma)
can occur only in pts on high-dose AZA
155
SEs of AZA
Leukopenia, thrombocytopenia, immunosuppression
Infection (scabies, HPV, HSV)
Teratogenicity
Hypersensitivity syndrome
Hepatotoxicity (rare)
156
Monitoring tests for pts on AZA
* Baseline pregnancy test & TB skin test
* Annual complete physical examination with particular attention to possible lymphoma & SCC
* CBC with differential & LFTs every 2 weeks for the first 2 months & every 2-3 months thereafter
157
The killed HBV vaccine administered to patients on AZA & CS has shown a decreased response
True / False?
True
158
Pts on AZA & anti-TNF-a are in increased risk of?
Hepatosplenic T-cell lymphoma
159
Indications of cyclosporine
Psoriasis
Off-label uses: atopic dermatitis, chronic
idiopathic urticaria, pyoderma gangrenosum, LP, bullous dermatoses, autoimmune connective tissue diseases, neutrophilic dermatoses, PRP
160
MoA of cyclosporine
Inhibits calcineurin
Forms complex with cyclophilin ==\>
↓ activity of NFAT-1 (nuclear factor of activated T cells)
==\> ↓IL-2 production
==\> CD4 & CD8 cells
161
Maximum dose of cyclosporine?
5mg/kg daily
Can be used continuously for up to 1 year maximum
For obese patients, ideal body weight should be used to
calculate starting dose
162
Cyclosporine SEs
5H 2N mnemonic
Hyperplasia gingival
Hepatotoxicity
Hyperglycemia
HTN
Hypertrichosis
Nephrotoxicity
Neuropathy
163
Other SEs of cyclosporine
Hyperuricemia (can precipitate gout)
Hypomagnesemia
Hyperkalemia
Hyperlipidemia
164
List the 2 MC dose and duration-dependent cyclosporine's SE
Nephrotoxicity
HTN
165
How can you avoid irreversible kidney damage from cyclosporine?
* Pts receive 2,5-5mg/kg daily
* Dose-adjustment when Cr rises 30% from baseline
* Treatment lasts \< 1 year
166
Management of cyclosporine-induced HTN
* Thought to be due to renal vasoconstriction
* NOT a CI to continuing therapy
* Prescribe CCB (nifedipine, isradipine)
==\>vasodilators that do not alter cyclosporine serum levels
167
Psoriasis pts on cyclosporine for \> 2 years are at ^risk of?
NMSC
168
What percentage of pts is free of cyclosporine SE?
56%
169
Management of cyclosporine dosage when Cr \>30% baseline value
* Recheck Cr level → if remains elevated \>30% ==\>
* ↓dose by at least 1 mg/kg for 4 weeks, then ==\>
* If Cr level drops back down to \<30% above
baseline, can continue therapy
* If it does not drop, then discontinue therapy; if it
returns to within 10% of baseline, cyclosporine can be resumed at lower dose
170
When should you discontinue cyclosporine tx?
When Cr levels \>50% baseline
discontinue therapy until level returns to baseline
171
Monitoring for pts on cyclosporine
* Baseline, BUN, CBC, LFTs, fasting lipid profile,
magnesium, potassium, and uric acid
* Obtain two baseline BP at least 1 day apart
and two baseline Cr values at least 1 day apart
* Reevaluation of labs & BP every 2 weeks for the first 1-2 months, then every 4-6 weeks with BP checked at every visit
172
Cyclosporine can be used successfully as monotherapy in which diseases?
Poststreptococcal pustulosis
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)
173
MoA of MTX
DHF reductase inhibitor
Prevents conversion of DHF to THF
Inhibits purine synthesis
174
Concomitant use of MTX & folic acid or leucovorin(folinic acid) results in?
↓MTX-induced adverse effects
↓GI adverse effects by 26% (nausea, vomiting, and
abdominal pain)
↓risk of LFT abnormalities by 76%
↓risk of pancytopenia
↑ability to tolerate MTX (↓MTX discontinuation rate
for any reason)
175
When is testing for MTX-induced hepatic fibrosis recommended?
Pts on high cumulative doses ≥ 1.5–4 g
Particularly for pts with preexisting liver disease, alcohol abuse, hepatitis C, psoriasis, or those who did not receive folic acid supplementation
176
Gold standard for testing of MTX-induced liver fibrosis?
Liver biopsy
177
Indications of MTX
* extensive, severe, debilitating, or recalcitrant psoriasis
* Sezary syndrome
Off-label uses:
* PLEVA, LyP, Pemphigus, Pemphigoid, Sarcoidosis, MF
* Autoimmune connective tissue diseases, cutaneous vasculitis
178
Absolute CIs to MTX
Pregnancy (category X)
Lactation
179
Relative CIs to MTX
* Unreliable patient
* Compromised renal function
* Hepatic disease
* Metabolic disease (obesity or DM)
* Severe hematologic abnormalities
* Man or woman contemplating conception (3 months off drug for men, off one ovulatory cycle for women)
* Immunodeficiency syndrome
* Active infectious disease or Hx of severe infectious that could reactivate
180
Pt on MTX comes to the office complaining about newly developed bumps in his hands over the last 2 months. Dx?
MTX-induced accelerated nodulosis
similar to rheumatoid nodules, but smaller and classically on fingers
Rx: Discontinuance of MTX
181
DD btw MTX-induced accelerated nodulosis & RA
* more rapid onset & growth
* smaller size of nodules
* different distribution of nodules
(MTX: hands,feet,ear vs periarticular region in RA)
182
SE of MTX
Pulmonary fibrosis
Nausea,anorexia \>\>diarrhea, vomiting, ulcerative stomatitis
Alopecia
Dizziness
Myelosuppression
183
Which drugs increase MTX risk of myelosuppression?
* Agents that inhibit folic acid metabolism
(TMP, sulfonamides, dapsone)
* Agents that displace plasma proteins
(tetracyclines, phenytoin, phenothiazines, sulfonamides, NSAIDs, salicylates)
184
Monitoring for pts on MTX
* CBC w/ differential, LFTs, Cr, BUN, viral hepatitis panel at baseline
* repeat weekly for first month (excluding the viral hepatitis panel), and gradually decrease frequency every 2 weeks × 2 months, every month × 2 months, every 3 months thereafter)
185
Preferable route of administration of MTX in the pediatric population?
Injectable form
Pediatric patients may have reduced oral absorption of
MTX when taken with various foods or have underlying diseases
186
What is radiation recall dermatitis?
toxic cutaneous reactions reappear on previously irradiated skin
can be seen in pts on MTX
187
Indications of mycophenolate mofetil
* FDA approved for renal, cardiac, and liver allograft rejection prevention
* Off-label dermatologic uses: psoriasis, atopic dermatitis, pemphigus, pemphigoid, autoimmune connective tissue diseases, vasculitis, lichen planus, and sarcoidosis
188
MoA of Mycophenolate mofetil
Binds and inhibits inosine monophosphate dehydrogenase
(key enzyme for the de novo synthesis of purines – which is essential in activated lymphocytes)
189
Absolute and relative CIs of mycophenolate mofetil
* Absolute: Pregnancy, Drug allergy
* Relative: Lactation, PUD, Hepatic or renal disease, concomitant use of cholestyramine, AZA
190
SE of mycophenolate mofetil
* Risk of carcinogenesis (lymphoma, lymphoproliferative disorders)
* Diarrhea, abdominal pain, N & V
* pseudo-Pelger-Huet anomaly (type of neutrophil dysplasia, predictor of neutropenia)
191
Indications of hydroxyurea
* CML, SCC of head & neck, sickle cell anemia, some forms of metastatic melanoma
* Off-label for: recalcitrant psoriasis, Sweet's syndrome, erythromelalgia, hypereosinophilic syndrome
192
SE of hydroxyurea
Megaloblastic anemia
Dermatomyositis like eruption
Leg ulcers
Hyperpigmentation of skin & nails
Radiation recall
Alopecia
193
Hydroxyurea induced leg ulcers and melanonychia
(ass/w prolonged use of hydroxyurea)
Resolve after drug discontinuation
194
Cyclophosphamide MoA
Alkylating agent
directly damaging DNA via cross-linking
Nitrogen mustard derivative
195
Indications of cyclophosphamide
* Mycosis fungoides
* Off-label: severe immunobullous
disease (e.g., ocular cicatricial pemphigoid), severe systemic vasculitides, neutrophilic dermatoses, and autoimmune connective tissue diseases
196
SE of cyclophosphamide
* Hemorrhagic cystitis (as a result of acrolein)
* ↑risk of transitional cell carcinoma of the bladder, non-Hodgkin’s lymphoma, leukemia, SCC
* N & V ( most common)
* ↑risk infertility: amenorrhea (27%–60%); premature ovarian failure (up to 80%)
197
Cutaneous SE of cyclophosphamide
* permanent pigmented band on the teeth
* anagen effluvium
* hyperpigmentation of skin and nails
198
Indications of antimalarials (chloroquine & hydroxychloroquine)
* SLE, malaria, and RA
* Off-label: particularly useful in disorders with significant lymphocytic infiltrates (polymorphous light eruptions, lymphocytic infiltrate of Jessner, lupus panniculitis, and discoid LE)
199
Absolute & relative CIs to antimalarials
* Absolute: Hypersensitivity to drug, retinopathy, myasthenia gravis (CQ)
* Relative: Pregnancy, lactation, severe blood dyscrasias, hepatic disfunction, retinal or neurological disorders
200
Mucocutaneous SE of antimalarials
* Yellow pigmentation of the skin (quinacrine)
* Drug-induced LP
* Morbilliform hypersensitivity eruption; may also
present as erythroderma or SJS
* Psoriasis exacerbation (CQ in particular)
* Bluish-gray to black hyperpigmentation (typically affecting the shins)
* Nail hyperpigmentation
201
SE of antimalarials
* Hemolysis in G6PD deficient population
* GI SEs
* Keratopathy, retinopathy, ciliary body dysfunction
202
Current eye monitoring recommendations for antimalarials
* Baseline examination including visual field testing
* Dilated examination and visual acuity testing within first year of starting therapy
* Dilated examination and visual acuity testing yearly after 5 years of treatment (some patients, such as the elderly, may require more frequent examinations)
203
Is G6PD testing necessary before the commencement of antimalarial agent tx?
No, risk of hemolysis for HCQ, CQ, and quinacrine with therapeutic doses il low
Hemolysis risk is mainly a concern for 8-aminoquinoline and primaquine
204
CQ and HCQ should be given together to maximize therapeutic effect
True / False?
False
CQ and HCQ should NOT be given simultaneously
Quinacrine may be added to HCQ or CQ for ↑therapeutic effect
205
Use of HCQ in pts with cutaneous lupus...?
Delays the time to fulfill criteria for SLE
206
Appropriate dose of antimalarials for porphyria cutanea tarda?
Low-dose HCQ or CQ may be used in porphyria cutanea tarda (i.e., 100–200 mg/day of HCQ vs 400 mg/day used for DLE)
207
Indications of dapsone
* dermatitis herpetiformis and leprosy
* Off-label: neutrophilic dermatoses (linear IgA dermatosis, bullous SLE, erythema elevatum diutinum, pyoderma gangrenosum,Sweet’s syndrome,neutrophilic urticaria,subcorneal pustular dermatosis/IgA pemphigus & Behcet’s syndrome), vasculitides
208
MoA of dapsone
Inhibits myeloperoxidase
→ ↓oxidative damage to normal tissue in various neutrophilic dermatoses
209
Important pharmacology points
Dapsone
* undergoes significant enterohepatic recirculation, remaining in the circulation 30 days after a single dose
* Hemolysis has been demonstrated in nursing infants of mothers taking dapsone
210
Important monitoring points
Dapsone
* Baseline G6PD level
* CBC w/ differential, LFTs, renal function tests, and UA at baseline
* Must monitor CBC very closely during “high-risk window” for agranulocytosis: CBC weekly for 4 weeks, then every 2 weeks until 3 months into treatment (agranulocytosis is most common in first 12 weeks of treatment)
* After 3 months, continue checking renal function, LFTs, and UA every 3 to 4 months
* Methemoglobin levels are needed if there is clinical suspicion of decreased oxygen circulation or anemia
211
Dapsone SE
* Hemolytic anemia and methemoglobinemia
* Agranulocytosis, the most serious idiosyncratic reaction to dapsone, usually occurs at 7 weeks(manifests as fever, pharyngitis, rarely sepsis)
* Peripheral neuropathy (predominantly distal motor)
* Nausea, gastritis, reversible cholestasis and hepatitis, and hypersensitivity syndrome
212
Most patients treated with dapsone for
dermatitis herpetiformis rapidly respond within...?
24 to 36 hours
bullous SLE also responds very well to Dapsone
213
Interesting facts for dapsone
* Cimetidine & vitamin E decreases risk of methemoglobinemia without affecting dapsone’s plasma level
* Methemoglobinemia emergency → use methylene blue
* Worsening of methemoglobinemia has been shown
intra- and postoperatively after both local amide and general anesthetic; vitamin C can be used when this occurs
214
